TW201026708A - Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers - Google Patents

Abstract

This invention concerns spiro azepane-oxazolidinones as voltage gated Kv1.3 potassium channel blockers, pharmaceutical compositions containing these compounds, methods for preparing the compounds, methods for preparing novel intermediates useful for their synthesis, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect diabetes and inflammatory neuropathies, including T-cell mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The compounds have formula (1): wherein the symbols have the meanings given in the specification.

Description

201026708 六、發明說明： 【發明所屬之技術領域】 發明領域 本發明涉及藥物和有機化學領域。本發明的實施方案 涉及並且提供了作為電壓門控性Κνΐ·3鉀通道阻斷劑的螺 氮雜環庚烷-喔唑烷酮（1_氧雜_3,8-二氮雜螺[4.6]十一烷-2-酮），以及中間體、製劑和方法。201026708 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of pharmaceuticals and organic chemistry. Embodiments of the present invention relate to and provide a spiroazepane-oxazolidinone (1_oxa-3,8-diazaspiro[4.6] as a voltage-gated Κνΐ·3 potassium channel blocker. ] undecane-2-one), as well as intermediates, formulations and methods.

L· Λ* J 發明背景 WO 00/25786(Merck & Co.，2000)、Schmalhofer等人 (Biochemistry，4卜 7781-7794，2002)、Baell(Expert Opin_ Ther. Patents，15(9) ’ 1209-1220，2005)*Harvey(J.Med. Chem· ’ 49(4) ’ 1433-144卜2006)均公開了基於苯甲醯氨基 亞甲基-環己基骨架（scaffold)的電壓門控性Kvl.3鉀通道阻 斷劑。 【發明内容】L· Λ* J BACKGROUND OF THE INVENTION WO 00/25786 (Merck & Co., 2000), Schmalhofer et al. (Biochemistry, 4 pp 7871-7794, 2002), Baell (Expert Opin_ Ther. Patents, 15(9) ' 1209 -1220, 2005) *Harvey (J. Med. Chem. '49(4) ' 1433-144b 2006) discloses voltage-gated Kvl based on benzamidine aminomethylene-cyclohexyl skeleton (scaffold). .3 potassium channel blocker. [Summary of the Invention]

公開内容 據發現，取代的螺氮雜環庚烷-噁唑烷酮（1-氧雜-3,8-二 氮雜螺[4·6]Η—烧-2-酮）是新的，並且是電壓門控性Kvl.3 鉀通道阻斷劑。本發明涉及式（1)的化合物，或互變異構體、 立體異構體或前述任一種的藥理學上可接受的鹽， 3 201026708DISCLOSURE OF THE INVENTION It has been found that a substituted spirozacycloheptane-oxazolidinone (1-oxa-3,8-diazaspiro[4.6]nonanthon-2-one) is novel and It is a voltage-gated Kvl.3 potassium channel blocker. The present invention relates to a compound of the formula (1), or a tautomer, a stereoisomer or a pharmacologically acceptable salt of any of the foregoing, 3 201026708

其中： -R!和R2獨立地為氫、氘、氟、CF3或烷基(Cu)，所述 烧基(Cw)未被取代或被一個或多個氟原子取代， -η為〇(零）、1或2， -R3選自鹵素、烷基(Ci-3)、CF3、CN、NH2、NHAc、 OH、OCH3 或 OCF3， -m為 0(零）、1、2或 3， -R4選自鹵素、烧基(Ci-3)、CF3、CN、NH2、NHAc、 OH、OCH3或OCF3’或(RJm與其所連接的苯環一起形成萘基。 在一些實施方案中’本發明還涉及式（丨）的化合物，或 互變異構體、立體異構體或前述任一種的藥理學上可接受 的鹽’其中Ri和R2獨立地為氫或甲基，η為0(零)或1，化為 鹵素，m為1或2，且R4選自鹵素、CF3、CN、〇CH3或〇CF3， 或(R4)m與其所連接的苯環一起形成萘基。 其他實施方案提供一種或多種式（1)的化合物或互變異 構體、立體異構體或前述任一種的藥理學上可接受的鹽， 其中&和^獨立地為氫、氘、氟、eh或烷基(Ci3)，所述 烧基（Cu)未被取代或被一個或多個氟原子取代；n為 201026708 〇(零）、1 或2 ’ R~3選自—素、烧基(Cw)、cf3、CN、NH2、 NHAc、OH、OCH3或 〇CF3 ; m為 0(零）、！、2或 3 ; R4選自 鹵素、烧基(C】-3)、CF3、CN、NH2、NHAc、OH、OCH3或 OCF3 ’或(R4)m與其所連接的苯環—'起形成茶基。 在一些實施方案中，本發明還涉及式（1)的化合物，或 互變異構體、立體異構體或前述任—種的藥理學上可接受 的鹽，其中^和尺2獨立地為氫或甲基，11為〇(零），心為 函素’ m為1或2，且尺4選自鹵素、CF3、cN、〇CH3或〇CF3， 或(R4)m與其所連接的苯環一起形成萘基。 其他實施方案提供式⑴的化合物或互變異構體、立體 異構體或前述任-制藥理學上可接受的鹽，所述化合物 選自： (5S)-8-[3,5-雙（三a甲基）笨甲醯基]_3_[(1S)小苯基乙 基]-1-氧雜-3,8-二氮雜螺[4.6]-十—烷_2__， (5R)-8-[3,5-雙（三I甲基）苯甲酿基]-3-[(lS)-l-笨基乙 基]-卜氧雜-3,8-二氮雜螺[4.6]-十一烷_2_嗣， (5R)-8-[3,5-雙（三氟甲基）苯曱酿基]_3[(1R)1笨基乙 基]-1-氧雜-3,8-二氧雜螺[4.6]-十一烷_2_酿j， (5S)-8'[3,5-雙（三氟甲基）笨甲醯基]-3-[(lR)-l-笨基乙 基]-1-氧雜-3,8-二氮雜螺[4.6]-十一烷_2_酮， (5S)_8-[3-氰基笨曱醯基]刊⑸」·苯基乙基]小氧雜 -3’8-—氮雜螺[46]十一烷_2_酮， (5R)-8-[3-氰基笨甲酿基]_3_[(1S)小苯基乙基H氧雜 -3’8-二氮雜螺[46]十一烷_2綱， 5 201026708 (5RW3_氰基笨甲醯基]·3·[_·1-笨基乙基Η-氧雜 -3,8-二氮雜螺[4·6]十—烷_2酮， (5S)_8_[3_氰基笨甲醜基]-3-[(lRH-笨基乙基Η-氧雜 -3’8-二氮雜螺[4.6]十—烷_2酮。 其他實施方案提供—種或多種式⑴的化合物或其藥理 千上可接_鹽’所述化合物為光學活性的對映異構體或 非對映異構體。 在-些實施方案中，本發明還涉及式⑴的化合物或其 藥理學上可接&的鹽’其中與射院輯中的氣原子相連 的碳原子為(R)或(S)對映異構體。 在一些實施方案中，本發明還涉及式（1)的化合物或其 藥理學上可接受的鹽，其巾中^的季螺·碳原子為(R)或(S) 對映異構體。 本發明的其他實施方案涉及式(V)、（Vi)或(vii)的化合物Wherein: -R! and R2 are independently hydrogen, hydrazine, fluorine, CF3 or alkyl (Cu), the alkyl group (Cw) is unsubstituted or substituted by one or more fluorine atoms, and -η is 〇 (zero ), 1 or 2, -R3 is selected from halogen, alkyl (Ci-3), CF3, CN, NH2, NHAc, OH, OCH3 or OCF3, -m is 0 (zero), 1, 2 or 3, -R4 Selected from halogen, alkyl (Ci-3), CF3, CN, NH2, NHAc, OH, OCH3 or OCF3' or (RJm forms a naphthyl group with the phenyl ring to which it is attached. In some embodiments, the invention also relates to A compound of the formula (丨), or a tautomer, a stereoisomer or a pharmacologically acceptable salt of any of the above, wherein Ri and R2 are independently hydrogen or methyl, and η is 0 (zero) or And is halogen, m is 1 or 2, and R4 is selected from halogen, CF3, CN, 〇CH3 or 〇CF3, or (R4)m forms a naphthyl group together with the benzene ring to which it is attached. Other embodiments provide one or more A compound or tautomer of the formula (1), a stereoisomer or a pharmacologically acceptable salt of any of the foregoing, wherein & and ^ are independently hydrogen, deuterium, fluorine, eh or alkyl (Ci3) , the alkyl group (Cu) is not replaced Substituted by one or more fluorine atoms; n is 201026708 〇 (zero), 1 or 2 ' R~3 is selected from the group consisting of - aryl, alkyl (Cw), cf3, CN, NH2, NHAc, OH, OCH3 or 〇CF3; m is 0 (zero), !, 2 or 3; R4 is selected from halogen, alkyl (C)-3), CF3, CN, NH2, NHAc, OH, OCH3 or OCF3 ' or (R4)m to which it is attached Benzene ring-'s formed into a tea base. In some embodiments, the invention also relates to a compound of formula (1), or a tautomer, a stereoisomer or a pharmacologically acceptable salt of any of the foregoing, Wherein ^ and the ruler 2 are independently hydrogen or methyl, 11 is 〇 (zero), the heart is a element 'm is 1 or 2, and the rule 4 is selected from halogen, CF3, cN, 〇CH3 or 〇CF3, or R4)m forms a naphthyl group together with the phenyl ring to which it is attached. Other embodiments provide a compound or tautomer, stereoisomer or any of the foregoing - pharmaceutically acceptable salts of formula (1) selected from the group consisting of : (5S)-8-[3,5-bis(tri-amethyl) benzoyl hydrazide]_3_[(1S) small phenylethyl]-1-oxa-3,8-diazaspiro[ 4.6]-Tetra-alkane_2__, (5R)-8-[3,5-bis(tri-Imethyl)benzyl]-3-[(lS)-l- stupid Ethyl]-pooxa-3,8-diazaspiro[4.6]-undecane_2_嗣, (5R)-8-[3,5-bis(trifluoromethyl)benzoquinone ]_3[(1R)1 stupidylethyl]-1-oxa-3,8-dioxaspiro[4.6]-undecane_2_ brewing j, (5S)-8'[3,5- Bis(trifluoromethyl)benzoamyl]-3-[(lR)-l-stylethyl]-1-oxa-3,8-diazaspiro[4.6]-undecane_2 Ketone, (5S)_8-[3-cyano aluminyl] publication (5)"·phenylethyl]sodium oxa-3'8-azaspiro[46]undecene-2-one, (5R)-8-[3-Cyano-Butyl]_3_[(1S)PhenylphenylethylH-oxa-3'8-diazaspiro[46]undecane_2, 5 201026708 (5RW3_cyanobenzamide)·3·[_·1-stylethylhydrazine-oxa-3,8-diazaspiro[4·6]deca-alkanone, (5S) _8_[3_Cyano-phenylidene]-3-[(lRH-stupylethylindole-oxa-3'8-diazaspiro[4.6]deca-alkanone). Other embodiments provide one or more compounds of formula (1) or a pharmacologically acceptable compound thereof. The compound is an optically active enantiomer or diastereomer. In some embodiments, the invention also relates to a compound of formula (1) or a pharmacologically acceptable salt thereof, wherein the carbon atom attached to the gas atom in the shot is (R) or (S) isomer. In some embodiments, the present invention is also a compound of formula (1) or a pharmacologically acceptable salt thereof, wherein the snail carbon atom of the oxime is (R) or (S) enantiomer. Further embodiments of the invention relate to compounds of formula (V), (Vi) or (vii)

其中Ri、R2、η和R3具有上述含義，這樣的化合物可以 用於合成式（1)的化合物。 其他實施方案提供下述化合物： 201026708Wherein Ri, R2, η and R3 have the above meanings, and such a compound can be used for the synthesis of the compound of the formula (1). Other embodiments provide the following compounds: 201026708

另一個實施方案提供製備式（1)的化合物的方法，所述 方法包括如下步驟： (i)用保護基保護六氫（1H)-氮雜環庚三烯-4-酮1，得到 式2的酮：Another embodiment provides a process for the preparation of a compound of formula (1), the process comprising the steps of: (i) protecting hexahydro(1H)-azephen-4-one 1 with a protecting group to give Formula 2 Ketone:

1 2 (ii)將式2的酮環氧化為式3的螺-環氧化物：1 2 (ii) epoxidation of the ketone of formula 2 to the spiro-epoxide of formula 3:

2 3 (iii)用式RNH2的胺4氨解式3的螺-環氧化物，得到式5 的氨基醇，其中R代表如下部分：2 3 (iii) Aminolysis of the spiro-epoxide of formula 3 with amine 4 of formula RNH2 affords the amino alcohol of formula 5 wherein R represents the following moiety:

其中心和112獨立地為氫、氘、氟、CF3或烷基(C^)，所 述烷基(Cm)未被取代或被一個或多個氟原子取代；η為 0(零）、1 或2 ; R3選自鹵素、烷基(Cm)、CF3、CN、ΝΗ2、 NHAc、OH、OCH3或 OCF3 ; m為 0(零）、1、2或 3， 7 201026708Its center and 112 are independently hydrogen, hydrazine, fluorine, CF3 or alkyl (C^), which is unsubstituted or substituted by one or more fluorine atoms; η is 0 (zero), 1 Or 2; R3 is selected from halogen, alkyl (Cm), CF3, CN, ΝΗ2, NHAc, OH, OCH3 or OCF3; m is 0 (zero), 1, 2 or 3, 7 201026708

3 5 (iv)在羰基化試劑存在下，經DMAP催化使氨基醇5閉 環形成螺-噁唑烷酮衍生物63 5 (iv) Amino alcohol 5 is cleaved by DMAP in the presence of a carbonylation reagent to form a spiro-oxazolidinone derivative 6

5 6 (v)將式6的螺-噁唑烷酮脫保護，得到式7的牝合物。 具體實施方案所提供的上述方法為，其中所述保護基 選自苄氧基羰基(Cbz)或叔丁氧基羰基(t_B〇c)。 其他實施方案提供包含式（1)的化合物或其藥谈學上可 接受的鹽的藥物。 進一步的實施方案提供用於治療糖尿病和炎疼性神經 病，包括T-細胞介導的自身免疫疾病，例如類風濞性關節 炎和多發性硬化的式（1)的化合物。 在些實施方案中，本發明還涉及组合物，所述組合 物包含至少一種藥學上可接受的載體或至少—種藥學上可 接受的輔助物質，或其兩種或更多種的組合；和藥理學活 性量的至少-種式⑴的化合㈣錢理學切接受的费。 進-步的實施方案提供式⑴的化合物用於製備藥物組 201026708 合物的用途，所述組合物用於治療糖尿病和炎症性神經 病，包括T-細胞介導的自身免疫疾病’例如類風濕性關節 炎和多發性硬化。 本發明的其他實施方案包括： 用於治療糠屎病和炎症性神經病，包括T-細胞介導的自 身免疫疾病，例如類風濕性關節炎和多發性硬化的方法， 所述方法包括尚需要這種治療的病人給予式（1)的化合物； 阻斷Kvl.3奸通道的方法，所述方法包括向需要阻斷 Kvl.3鉀通道的受治療者給予藥學上有效量的式（1)的化合物。 本發明進一少涉及聯合治療法，其包括將式（1)的化合 物，或包含式（1)的化合物的藥物組合物或製劑與另外的一 種或多種治療劑同時或依次給藥，或作為與另外的一種或 多種治療劑的聯合制劑給藥，從而用於治療一種或多種所 列的病症。可以在給予本發明的化合物之前、同時或之後 給予所述另外的一種或多種治療劑。 本發明還提供用於治療糖尿病和炎症性神經病’包括 T-細胞介導的自身免疫疾病，例如類風濕性關節炎和多發 性硬化的化合物、藥物組合物、試劑盒和方法，所述方法 包括向需要這種治療的病人給予式（1)的化合物。 本發明化合物具有Kvl.3鉀通道阻斷活性。本發明化合 物的抑制活性可以例如使用本文中描述的或現有技術中已 知的一個或多個試驗而容易地證實。 本發明還提供製備本發明化合物的方法和用於那些方 法中的中間體。 9 201026708 如果希望，可以借助任何適當的分離或純化方法，例 如過渡、萃取、結晶、柱色譜、薄層色譜、厚層色譜、製 備性低或高-壓液相色譜，或這些方法的組合來實現本文中 描述的化合物和中間體的分離和純化。適當的離析和分離 方法的具體示例可以來自製備和實施例。但是，當然還可 以使用其他等價的離析或分離方法。 本發明的化合物可以含有一個或多個不對稱中心，並 因此可以為外消旋物和外消旋混合物、單個的對映異構 體、非對映異構體混合物和單個的非對映異構體。本發明 的所有化合物在其季螺-碳原子上都含有至少一個手性中 心。絕對手性未知時的手性被稱作“構型1”，另一個對映異 構體被稱作“構型2”。“構型1”和“構型2”都可以相應地指定 為(R)或(S)。 取決於各種取代基的性質，分子可以具有額外的不對 稱中心。每個這種不對稱中心將獨立地產生兩個光學異構 體。無論是在混合物中，還是為純的或部分純化的化合物， 所有可能的光學異構體、對映異構體和非對映異構體都屬 於本發明的範圍。本發明包括這些化合物的所有這些異構 形式。式（1)顯示了一類化合物的結構，其沒有顯示優選的 立體化學構型。如所屬領域已知的，可以通過其中公開的 方法的適當變型實現這些光學異構體的單獨合成，或其色 譜分離。對結晶產品或結晶中間體(如果必要，用含有不對 稱中心且絕對構型已知的試劑對其進行衍生化）進行X -射 線結晶法可以確定其絕對立體化學構型。可以通過所屬領 10 201026708 域公知的方法將所述化合物的外消旋混合物分離為單獨的 對映異構體，例如將化合物的外消旋混合物偶合為對映異 構純的化合物以形成非對映異構體混合物，之後用標準方 法’例如分步結晶法或色譜法分離單個的非對映異構體。 還可以借助所屬領域公知的採用手性固定相的色譜法直接 分離所述化合物的外消旋混合物。可選地，通過所屬領域 公知的方法’使用光學純的原料或已知構型的試劑通過立 體選擇性合成可以獲得化合物的任何對映異構體。 式（1)的化合物的順式和反式異構體或其藥學上可接受 的鹽也屬於本發明，這也適用於式(1)的化合物的互變異構體。 所述化合物的一些結晶形式可以作為多晶形物存在， 這些也意圖包括在本發明中。PET或SPECT能夠檢測出來的 同位素-標έ己的式（1)的化合物也落在本發明的範圍内。這也 適用於以Pc]-、[HC]_、[3η]_、[丨8f]_、[⑵卟或其他同位素 富集原子標記的、適用於受體結合或代謝研究的式（1)的化 合物。 本發明的化合物還可以在神經功能、功能障礙和疾病 的生物化學研究中用作試劑或標準物。 L· 爽 ^ 定義 用於描述本發明的化合物的一般術語具有其通用含 義。本文中所用的術語烷基指單價飽和的支鏈或直鏈的烴 鍵。除非另外說明，否則這種鏈可以含有1至18個碳原子。 這樣的烷基的代表是甲基、乙基、丙基、異丙基、丁基、 11 201026708 異丁基、仲丁基、叔丁基、戊基、異戊基、新戊基、己基、 異己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、 十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、 十八炫《基等。备限疋為低級”時，所述院基含有1至6個石炭 原子。同樣的碳含義適用於母體術語“烷烴”，並適用於衍 生的術語例如“烧氧基”。各種含烴部分的碳含量以首碼表 示，指出了在所述部分中碳原子的最小和最大數值，即首 碼Cx-y定義的存在的碳原子數為整數“X”至整數“y”，含端 值。“烷基(Ci-3)”例如包括甲基、乙基、正丙基或異丙基，“烷 基(Cm)”包括“曱基、乙基、正丙基、異丙基、正丁基、2_ 丁基、異丁基或叔丁基’’。 “鹵代或鹵素”指氣代、氟代、溴代或蛾代；“雜炫基、 雜芳基”等中使用的“雜”包括含有一個或多個N、〇或5原 子。“雜烷基”包括在任意位置上帶有雜原子的烷基，並因 此包括結合了N的、結合了〇的或結合了^的烷基。 術語“取代的”意指指定的基團或部分含有一個或多個 取代基。其中任何基團可以帶有多個取代基，並且可以提 供多個可能的取代基，所述取代基各自獨立地進行選擇， 不一定相同。術語“未取代的”意指指定的基團不含有取代 基。根據取代基的定義，術語“獨立地，，意指當可能有多於 一個的這種取代基時，其彼此可以相同或不同。 本文中所用的作為另一個基團的一部分的術語“氧 基、硫基和羰基分別指氧原子、硫原子和羰基(c=〇)， 其作為兩個基®例如錄、氧基絲、硫院基、叛基烧基 12 201026708 等的連接基。本文中單獨或作為另一個基團的一部分使用 的術語“氨基”指可以為端基或為兩個其他基團的連接基的 氮原子，其中所述基團可以為伯、仲或叔(分別為兩個氫原 子鍵合在所述氮原子上、一個氫原子鍵合在所述氮原子上 和無氫原子鍵合在所述氮原子上）胺。為了提供更簡明的描 述’術語“化合物或‘多種化合物”包括互變異構體、立體 異構體或藥理學上可接受的鹽，在沒有明確提及的時候也 是如此。 術語“形式”包括所有固體：多晶型物、溶劑合物和無定 形形式。“晶體”指相同化合物的各種固體形式，例如多晶 型物、溶劑合物和無定形形式。“共晶”是指具有獨特晶格 的多組分晶體：由中性化合物製備的新化學物質。“無定形 形式”是指不具有長週期結構的非結晶物質，其通常不會產 生獨特的X-射線衍射圖案。Byrn(Pharmaceutical Research， 12⑺’945-954 ’ 1995)和 Martin(“Remington: The Science and5 6 (v) Deprotection of the spiro-oxazolidinone of Formula 6 to give a chelate of Formula 7. DETAILED DESCRIPTION OF THE INVENTION The above process is provided wherein the protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (t_B〇c). Other embodiments provide a medicament comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof. A further embodiment provides a compound of formula (1) for use in the treatment of diabetes and inflammatory neuropathy, including T-cell mediated autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. In some embodiments, the present invention also relates to a composition comprising at least one pharmaceutically acceptable carrier or at least one pharmaceutically acceptable auxiliary substance, or a combination of two or more thereof; The pharmacologically active amount of at least the compound of the formula (1) (iv) the fee for the acceptance of the money. Further embodiments provide a use of a compound of formula (1) for the preparation of a pharmaceutical group 201026708 for the treatment of diabetes and inflammatory neuropathy, including T-cell mediated autoimmune diseases such as rheumatoid Arthritis and multiple sclerosis. Other embodiments of the invention include: methods for treating rickets and inflammatory neuropathies, including T-cell mediated autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, including the need for this The treated patient is administered a compound of formula (1); a method of blocking Kvl.3, which comprises administering to a subject in need of blocking the Kvl.3 potassium channel a pharmaceutically effective amount of formula (1) Compound. The invention further relates to a combination therapy comprising administering a compound of formula (1), or a pharmaceutical composition or formulation comprising a compound of formula (1), simultaneously or sequentially with one or more additional therapeutic agents, or as A further combination of one or more therapeutic agents is administered to treat one or more of the listed conditions. The additional one or more therapeutic agents can be administered prior to, concurrently with, or subsequent to administration of the compound of the invention. The invention also provides compounds, pharmaceutical compositions, kits and methods for treating diabetes and inflammatory neuropathy including T-cell mediated autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, including A compound of formula (1) is administered to a patient in need of such treatment. The compounds of the invention have Kvl.3 potassium channel blocking activity. The inhibitory activity of the compounds of the invention can be readily demonstrated, for example, using one or more of the assays described herein or known in the art. The invention also provides methods of preparing the compounds of the invention and intermediates useful in those methods. 9 201026708 If desired, any suitable separation or purification method can be used, such as transition, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of these methods. The isolation and purification of the compounds and intermediates described herein are achieved. Specific examples of suitable separation and separation methods can be derived from the preparations and examples. However, it is of course also possible to use other equivalent methods of separation or separation. The compounds of the invention may contain one or more asymmetric centers and may therefore be racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomeric Structure. All of the compounds of the present invention contain at least one chiral center on their quaternary-carbon atoms. The chirality when the absolute chirality is unknown is called "configuration 1", and the other enantiomer is called "configuration 2". Both "Configuration 1" and "Configuration 2" can be designated as (R) or (S), respectively. Depending on the nature of the various substituents, the molecule may have an additional asymmetry center. Each such asymmetric center will independently produce two optical isomers. All possible optical isomers, enantiomers and diastereomers are within the scope of the invention, whether in the mixture or as pure or partially purified compounds. The present invention includes all such isomeric forms of these compounds. Formula (1) shows the structure of a class of compounds which do not show a preferred stereochemical configuration. The individual synthesis of these optical isomers, or their chromatographic separation, can be achieved by appropriate variations of the methods disclosed therein, as is known in the art. The absolute stereochemical configuration can be determined by X-ray crystallization of a crystalline product or a crystalline intermediate (if necessary, by derivatization with an agent having an asymmetric center and an absolute configuration). The racemic mixture of the compound can be separated into the individual enantiomers by methods well known in the art of 10 201026708, for example by coupling a racemic mixture of the compound to an enantiomerically pure compound to form a non-pair The mixture of the isomers is then separated by standard methods such as fractional crystallization or chromatography to separate the individual diastereomers. It is also possible to directly separate the racemic mixture of the compounds by means of chromatography using chiral stationary phases well known in the art. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. The cis and trans isomers of the compound of the formula (1) or a pharmaceutically acceptable salt thereof are also in the present invention, and this also applies to the tautomer of the compound of the formula (1). Some crystalline forms of the compounds may exist as polymorphs, and these are also intended to be included in the present invention. Compounds of formula (1) which are detectable by PET or SPECT and which are isotopes - are also within the scope of the invention. This also applies to formula (1) suitable for receptor binding or metabolism studies with Pc]-, [HC]_, [3η]_, [丨8f]_, [(2)卟 or other isotopically enriched atoms. compound of. The compounds of the invention may also be used as reagents or standards in biochemical studies of neurological function, dysfunction and disease. L· Shuang ^ Definitions The general terms used to describe the compounds of the present invention have their general meanings. The term alkyl as used herein refers to a monovalent saturated branched or straight chain hydrocarbon bond. Unless otherwise stated, such chains may contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, 11 201026708 isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, Isohexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, Eighteen dazzling "base." When the threshold is "lower", the yard contains 1 to 6 carbon atoms. The same carbon meaning applies to the parent term "alkane" and applies to derived terms such as "alkoxy". The carbon content is expressed in the first code, indicating the minimum and maximum values of the carbon atoms in the portion, that is, the number of carbon atoms defined by the first code Cx-y is an integer "X" to an integer "y", including the terminal value. "Alkyl (Ci-3)" includes, for example, methyl, ethyl, n-propyl or isopropyl, and "alkyl (Cm)" includes "indenyl, ethyl, n-propyl, isopropyl, n-butyl" Base, 2_butyl, isobutyl or tert-butyl ''. "Halo or halogen" means a gas, fluoro, bromo or moth; "hetero" as used in "hetero, heteroaryl" and the like includes one or more N, hydrazine or 5 atoms. "Heteroalkyl" includes alkyl groups bearing a hetero atom at any position, and thus includes N-bonded, fluorene-bonded or bonded alkyl groups. The term "substituted" means that the specified group or moiety contains one or more substituents. Any of these groups may carry a plurality of substituents, and a plurality of possible substituents may be provided, each of which is independently selected, not necessarily the same. The term "unsubstituted" means that the specified group does not contain a substituent. According to the definition of a substituent, the term "independently, means that when there may be more than one such substituent, they may be the same or different from each other. The term "oxy" as used herein as part of another group. The thio group and the carbonyl group refer to an oxygen atom, a sulfur atom and a carbonyl group (c=〇), respectively, which serve as a linking group of two groups such as, for example, a siloxane, a thiol group, a thiol group 12 201026708 and the like. The term "amino" as used herein, alone or as part of another group, refers to a nitrogen atom which may be a terminal group or a linking group of two other groups, wherein the group may be primary, secondary or tertiary (respectively An amine in which two hydrogen atoms are bonded to the nitrogen atom, a hydrogen atom is bonded to the nitrogen atom, and no hydrogen atom is bonded to the nitrogen atom. In order to provide a more concise description, the term "compound" or "a plurality of compounds" includes tautomers, stereoisomers or pharmacologically acceptable salts, as is not explicitly mentioned. The term "form" includes all solids: polymorphs, solvates, and amorphous forms. "Crystal" refers to various solid forms of the same compound, such as polymorphs, solvates, and amorphous forms. "Cyctic" refers to a multi-component crystal with a unique crystal lattice: a new chemical prepared from a neutral compound. "Amorphous form" refers to an amorphous material that does not have a long period structure, which typically does not produce a unique X-ray diffraction pattern. Byrn (Pharmaceutical Research, 12(7)'945-954 '1995) and Martin ("Remington: The Science and

Practice of Pharmacy”，Mack Publishing Company，19th版， Easton ’ Pa，第 2卷，第 83章，1447-1462，1995)對晶型進 行了一般性描述。“多晶型物”是指化合物可以以不同的晶 體堆積方式進行結晶的晶體結構，其中所有堆積方式都具 有相同的元素組成。多晶型性是一種常見現象，其受多種 結晶條件例如溫度、過飽和水準、雜質存在、溶劑極性、 冷卻速率的影響。不同的多晶型物通常具有不同的χ_射線 衍射圖案、固態NMR譜圖、紅外或拉曼譜圖、熔點、密度、 硬度、晶形、光學和電學性質、穩定性和溶解性。重結晶 13 201026708 溶劑、結晶速率、貯存溫度和其他因素可能會導致一種結 晶形式為主要形式。 為了提供更簡明的描述，本文中給出的一些定量描述 沒有用“約”進行限制。應該理解，無論是否明確使用術語 “約”，本文中給出的每個數量都意指實際給出的數值，並 且其還意指所屬領域普通技術人員能夠合理推斷的這種給 定值的近似值，包括這種給定值的試驗或測量條件所導致 的近似值。 在本申請的說明書和申請專利範圍中，措辭“包括”和 所述措辭的變型，例如“包含”和“含有”，並不意圖排除其 他添加劑、組分、整數或步驟。 雖然可以將式（1)的化合物按照原化學品形式給藥，但 是優選其為“藥物組合物”。根據進一步的方面，本發明提 供一種藥物組合物，所述組合物包含至少一種式（1)的化合 物、至少一種其藥學上可接受的鹽或前述任一種的混合 物，以及一種或多種其藥學上可接受的載體，並且可以含 有或不含有一種或多種其他治療成分。所述載體必須是“可 接受的”，意思是與製劑的其他試劑可相容並且對其受用者 無毒。本文中所用的術語“組合物”包括包含預定量或預定 比例的指定成分的產品，以及指定量的指定成分經組合而 直接或間接產生的任何產品。就藥物組合物而言，該術語 包括包含一種或多種活性成分和任選的包含惰性成分的載 體的產品，以及任意兩種或多種成分經組合、配合或聚集 而直接或間接產生的任何產品。通常，按照下述方式製備 14 201026708 藥物組合物：使活性成分與液體載體或精細分散的固體載 體或二者均勻、密切結合，之後如果必要將所述產品成型 為希望的製劑。所述藥物組合物包括足量的活性目標化合 物’從而對疾病的進展或症狀產生希望的作用。因此，本 發明的藥物組合物包括由本發明的化合物與藥學上可接受 的載體混合而制得的任何組合物。“藥學上可接受的”意指 載體、稀釋劑或赋形劑必須與所述製劑的其他成分相容並 且對其受用者無毒。 在本申請的背景下’術語“聯合制劑，，包括真正的聯 合’意指式（1)的化合物與一種或多種其他藥物被物理結合 在一種製劑，例如片劑或注射液中，以及“多部分試劑盒”， 其包含在分開的劑型中的式（1)的化合物和一種或多種其他 藥物，加上使用說明，並且帶有或不帶有其他有助於組分 化合物給藥的手段，例如標籤或圖樣。對於真正的聯合， 所藥物療法被定義為同時給藥》“多部分試劑盒，，的内容物 可以同時給藥或以不同的時間間隔給藥。是伴隨療法還是 順序療法取決於使用的其他藥物的特性、諸如作用開始和 持續時間的特性、血漿水準、清除性等，並且取決於所述 疾病、其階段和病人個體的特性。 劑量。下面確定本發明化合物作為電壓門控性Kvl 3通 道抑制劑的效力。根據測定的給定的式（1)的化合物的效 力，可以估計出理論的最低有效劑量。當化合物濃度等於 測定的抑制常數的2倍時，所述化合物可以阻斷將近1〇〇% 的1^1.3通道。將該濃度換算為每kg病人的化合物mg數，可 15 201026708 以得到理論的最低有效劑量，其中假定為理想的生物利用 率。藥物代謝動力學、藥效學和其他需要考慮的事項可能 會使實際給藥的劑量改變至更高或更低值。活性成分的常 用曰劑量可以在寬範圍内變化並且取決於多種因素，例如 相關適應症、給藥途徑、病人的年齡、體重和性別，其可 以由内科醫生確定。通常，單次或以多個單獨劑量給藥於 病人時，總劑量可以為例如每曰0.001至10 mg/kg體重，更 通常為每日0.01至1，000 mg活性成分總量。向需要治療的病 人給藥這種劑量，每日1至3次，或按照藥效需要而多次給 藥，給藥時間為至少兩個月，更通常至少六個月，或長期 給藥。 本文中所用的術語“治療有效量”指在治療通過給予本 發明的組合物可以治療的症狀時，治療劑的量。該量包括 在組織體系、動物或人體中足以顯示可檢測的治療或緩解 反應的量。所述效果可以包括例如治療本文中所列的病 症。用於患者的精確的藥學上有效量取決於患者的體型和 健康狀況、待治療的病症的性質和程度、主治醫生（研究人 員、獸醫、醫生或其他臨床醫師）的建議，和所選的給藥療 法或療法組合。因此，提前指定確切的藥學上有效量也沒 有用。“藥物鹽”指在同一結晶結構中含有活性藥物成分 (API)以及另外的非毒性分子物質的酸：鹼配合物。術語“藥 學上可接受的鹽”指下述鹽：在合理的醫學判斷範圍内，適 用於與人和低級動物的組織接觸而不產生過度的毒性、輻 射、過敏反應等並且具有合理的利益/風險比。藥學上可接 201026708 受的鹽是關領域公知的。4祕要分離和減本發明 的化合物則可以就地製述鹽，或通過使…、藥學上可 接受的非毒性驗或酸，包括無機或有機驗和無機或有機酸 反應來製備（8零，^.:“聊__价318浙’，了· Phannaceutical Science，66，1]9(1977)。用在藥學上可接 受的鹽中的常規陰離子包括：氯離子、溴離子、硫酸根、 硝酸根、磷酸根、碳酸氫根、甲磺酸根、乙磺酸根、羥乙 基磺酸鹽(isothianate)、甲苯磺酸根、萘磺酸根、苯續酸鹽、 乙酸根、丙酸根、馬來酸根、苯甲酸根、水楊酸根、富馬 酸根、檸檬酸根、乳酸根、馬來酸根、酒石酸根、雙羥萘 酸根、琥珀酸根、乙醇酸根、己酸根、辛酸根、癸酸根、 硬脂酸根、油酸根、天冬氨酸根和谷氨酸根。在藥學上可 接受的鹽中用作反離子的常規陽離子包括：鈉、鉀、鈣、 鎂、鋰、鋅、鋁、精氨酸、賴氨酸、組胺酸、三乙胺、乙 醇胺、三乙醇胺、亞乙基二胺、甲葡胺、普魯卡因和N，N，-雙苄基-1,2-乙二胺(benzathine)。 使所述鹽與鹼或酸接觸並從常規物質中分離母體化合 物則可以使“游離鹼”形式得以再生。所述化合物母體形式 的某些物理性質，例如在極性溶劑中的溶解性與各種鹽形 式有所不同，但是另外地，用於本發明的目的時所述鹽與 化合物母體形式是等效的。 本文中所用的術語“治療，’指對人類病症或疾病的任何 治療，包括：（1)抑制疾病或病症，即阻止其發展，（2)緩解 疾病或病症’即使病症復原，或(3)終止疾病的症狀。術語“抑 17 201026708 制”包括其普遍接受的含義，包括限制、緩解、改善，和減 緩、終止或逆轉進程、嚴重性或導致的症狀。如本文中所 用的’術§吾醫學療法意圖包括在人體内或體外進行的診 斷和治療法。 實施例1 :分析方法 除非另外說明，否則使用Bruker ARX 400(4 : 400 MHz，13C : 100 MHz)，在300 K下，於指示的溶劑中確定 核磁共振 s普圖（H NMR和 C NMR ’ APT)。在 Varian Inova 500光譜儀上進行19F NMR和13C NMR試驗，其中所述光譜 儀使用 5 mm SW探針於 11.74 7(4-499.9 MHz; 13C，125.7 MHz ; 19F ’ 50.7 Mhz ’ 470.4 MHz)下操作。在得自 CambridgePractice of Pharmacy", Mack Publishing Company, 19th Edition, Easton 'Pa, Vol. 2, Chapter 83, 1447-1462, 1995). A general description of the crystalline form. "Polymorph" means that the compound can Different crystal packing methods are used to crystallize the crystal structure, all of which have the same elemental composition. Polymorphism is a common phenomenon, which is affected by various crystallization conditions such as temperature, supersaturation level, presence of impurities, solvent polarity, cooling rate The different polymorphs usually have different χ-ray diffraction patterns, solid state NMR spectra, infrared or Raman spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Recrystallization 13 201026708 Solvents, crystallization rates, storage temperatures and other factors may cause a crystalline form to be predominant. In order to provide a more concise description, some of the quantitative descriptions given herein are not limited by "about." It should be understood that Whether or not the term "about" is used explicitly, each quantity given herein is intended to be actually given. Value, and it also means an approximation of such a given value that can be reasonably inferred by one of ordinary skill in the art, including approximations resulting from the test or measurement conditions of such a given value. In the specification and claims of the present application The wording "comprises" and variations of the wording, such as "comprises" and "comprising", is not intended to exclude other additives, components, integers or steps. Although the compound of formula (1) can be given as the original chemical form Medicament, but preferably it is a "pharmaceutical composition." According to a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1), at least one pharmaceutically acceptable salt thereof or the foregoing a mixture of any one, and one or more pharmaceutically acceptable carriers thereof, and may or may not contain one or more additional therapeutic ingredients. The carrier must be "acceptable", meaning that it may be compatible with other agents of the formulation. Is not toxic to its users. The term "composition" as used herein includes the inclusion of a predetermined amount or a predetermined ratio. A product of a specified ingredient, and any product produced directly or indirectly by a combination of specified amounts of the specified ingredients. For pharmaceutical compositions, the term includes a product comprising one or more active ingredients and, optionally, a carrier comprising an inert ingredient, And any product produced directly or indirectly by combining, blending or agglomerating any two or more of the ingredients. Typically, the pharmaceutical composition is prepared as follows: 201026708 pharmaceutical composition: the active ingredient with a liquid carrier or a finely divided solid carrier or both Uniform, intimately combined, and then shaped into a desired formulation if necessary. The pharmaceutical composition comprises a sufficient amount of the active target compound' to produce a desired effect on the progression or symptoms of the disease. Thus, the pharmaceutical combination of the present invention Included are any compositions made by combining a compound of the invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and non-toxic to the user. In the context of the present application, the term 'term combination', including a true combination, means that a compound of formula (1) is physically associated with one or more other drugs in a formulation, such as a tablet or injection, and "multiple a kit of parts comprising a compound of formula (1) and one or more other drugs in separate dosage forms, with instructions for use, with or without other means of facilitating administration of the component compounds, For example, a label or a pattern. For a true combination, the drug therapy is defined as a simultaneous administration of a "multi-part kit," and the contents can be administered simultaneously or at different time intervals. Whether the concomitant therapy or the sequential therapy depends on the characteristics of other drugs used, such as the characteristics of the onset and duration of action, plasma levels, clearance, and the like, and depends on the disease, its stage, and the characteristics of the individual patient. dose. The potency of the compounds of the invention as voltage-gated Kvl 3 channel inhibitors is determined below. Based on the determined potency of a given compound of formula (1), the theoretical minimum effective dose can be estimated. When the compound concentration is equal to 2 times the determined inhibition constant, the compound can block nearly 1% of the 1^1.3 channel. This concentration is converted to the number of mg of compound per kg of patient, which can be 15 201026708 to obtain the theoretical minimum effective dose, which is assumed to be the ideal bioavailability. Pharmacokinetics, pharmacodynamics, and other considerations may change the actual administered dose to a higher or lower value. The usual dose of active ingredient can vary widely and depends on a variety of factors, such as the relevant indication, the route of administration, the age, weight and sex of the patient, which can be determined by the physician. Generally, when administered to a patient in a single or multiple separate doses, the total dose can be, for example, from 0.001 to 10 mg/kg body weight per ounce, more typically from 0.01 to 1,000 mg total active ingredient per day. The dose is administered to a patient in need of treatment, one to three times a day, or multiple times as needed, for a period of at least two months, more usually at least six months, or long-term administration. The term "therapeutically effective amount" as used herein refers to the amount of a therapeutic agent when treating a condition treatable by administration of a composition of the invention. This amount includes an amount sufficient to exhibit a detectable therapeutic or palliative response in a tissue system, animal or human. Such effects can include, for example, treating the conditions listed herein. The precise pharmaceutically effective amount for a patient depends on the size and health of the patient, the nature and extent of the condition to be treated, the advice of the attending physician (researcher, veterinarian, doctor or other clinician), and the selected Combination of medications or therapies. Therefore, it is not useful to specify the exact pharmaceutically effective amount in advance. "Pharmaceutical salt" refers to an acid:base complex containing the active pharmaceutical ingredient (API) and additional non-toxic molecular substances in the same crystalline structure. The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for contact with tissues of humans and lower animals without causing excessive toxicity, radiation, allergic reactions, etc. and having reasonable benefits/ Risk ratio. Pharmaceutically acceptable 201026708 Salts are well known in the art. 4 secret separation and reduction of the compounds of the invention can be prepared in situ, or by ..., pharmaceutically acceptable non-toxic test or acid, including inorganic or organic and inorganic or organic acid reaction (8 zero , ^.: "Talk __ Price 318 Zhejiang", Phannaceutical Science, 66, 1] 9 (1977). Conventional anions used in pharmaceutically acceptable salts include: chloride, bromide, sulfate, Nitrate, phosphate, bicarbonate, mesylate, ethanesulfonate, isothianate, tosylate, naphthalenesulfonate, benzoate, acetate, propionate, maleate Benzoate, salicylate, fumarate, citrate, lactate, maleate, tartrate, pamoate, succinate, glycolate, hexanoate, octanoate, citrate, stearate, Oleate, aspartate and glutamate. Conventional cations used as counterions in pharmaceutically acceptable salts include: sodium, potassium, calcium, magnesium, lithium, zinc, aluminum, arginine, lysine , histidine, triethylamine, ethanolamine, triethanol , ethylenediamine, meglumine, procaine, and N,N,-bisbenzyl-1,2-ethanediamine (benzathine). The salt is contacted with a base or acid and from a conventional substance. Separation of the parent compound allows regeneration of the "free base" form. Certain physical properties of the parent form of the compound, such as solubility in polar solvents, differ from various salt forms, but otherwise, for use in the present invention The salt is equivalent to the parent form of the compound for purposes. The term "treating," as used herein, refers to any treatment of a human condition or disease, including: (1) inhibiting a disease or condition, ie preventing its development, (2) Relieving a disease or condition 'even if the condition is rehabilitated, or (3) terminating the symptoms of the disease. The term "17 17 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. Or caused symptoms. As used herein, the medical therapy is intended to include the diagnosis and treatment performed in vivo or in vitro. Example 1: Analytical methods Bruker is used unless otherwise stated. ARX 400 (4: 400 MHz, 13C: 100 MHz), nuclear magnetic resonance spectroscopy (H NMR and C NMR 'APT) was determined in the indicated solvent at 300 K. 19F NMR and on a Varian Inova 500 spectrometer 13C NMR test in which the spectrometer was operated using a 5 mm SW probe at 11.74 7 (4-499.9 MHz; 13C, 125.7 MHz; 19F '50.7 Mhz '470.4 MHz).

Isotope Laboratories Ltd的氘代氣仿或二氣甲烷中確定譜 圖。化學位移（δ)從四曱基碎烧向低磁場方向以ppm表示 (4，13C)或CC13F(19F)。偶合常數J以Hz表示。NMR譜的峰 形標記為符號“q”（四重峰）、“dq”（兩個四重峰）、“t”（三重 峰）、“dt”(兩個三重峰）、“d”(雙重峰）、“dd”(兩個雙重峰）、 “s”(單峰）、“bs”(寬的單峰)和“m”(多重峰）。將樣品與一滴 D20混合後鑒別出NH和OH信號。 快速色譜法指使用指示的洗脫劑和矽膠（Acros : 0.030-0.075 mm，或Merck石夕膠60: 0.040-0.063 mm)進行純化。 使用矽膠60(0.063-0.200 mm，Merck)實施柱色譜法。 在BtichiB-545溶點儀上記錄炫點。 使用薄層色譜法(TLC)，用指定的洗脫液在矽膠塗敷的 塑膠片（Merck預塗布矽膠60 F254)上監測反應。使用UV光 201026708 (254 nm)或12使點顯現。 採用JEOL JMS-SX/SX 102 A串聯質譜儀測量質譜和精 確的品質，其中所述質譜儀使用快原子轟擊（Fast Atom Bombardement)(FAB)。使用分辨能力為1〇,〇〇〇(1〇%峰谷定 義）的高解析度FAB質譜分析法。 在C18柱（Inertsil ODS-3，粒度3 mm ; 4.6 mm 50 mm) 上進行分析性HPLC，使用下列洗脫梯度：5%至95%CH3CN 水溶液的線性梯度，歷時5分鐘，其中所述的95%CH3CN含 有0.04%HC02H，然後以2.0 ml min-1的速率使含有 0.04%HC02H的95%CH3CN水溶液流過2分鐘。在λ = 254 rim 處檢測產品。 液相色譜-質譜(LC-MS): “方法W” LC-MS系統由Waters 15 25 μ泵及與其相連的waters 2777自動採樣器組成。LC方法為： 步驟 總時間 流速(μΐ/min) A(%) B(%) 0 0.2 1600 90 10 1 2.5 1600 0 100 2 2.8 1600 0 100 3 2.9 1600 90 10 4 3.10 1600 90 10 5 3.11 500 90 10The spectrum was determined in the deuterated gas or two gas methane of Isotope Laboratories Ltd. The chemical shift (δ) is expressed in ppm from tetrahydrocarbazone to low magnetic field (4,13C) or CC13F (19F). The coupling constant J is expressed in Hz. The peak shape of the NMR spectrum is marked by the symbols "q" (quadruple peak), "dq" (two quartlets), "t" (triplet), "dt" (two triplets), "d" ( Double peak), "dd" (two double peaks), "s" (single peak), "bs" (wide single peak), and "m" (multiple peak). The NH and OH signals were identified by mixing the sample with a drop of D20. Flash chromatography refers to purification using the indicated eluent and tannin (Acros: 0.030-0.075 mm, or Merck Shiki 60: 0.040-0.063 mm). Column chromatography was carried out using silicone 60 (0.063-0.200 mm, Merck). The highlights were recorded on a Btichi B-545 dot spectrometer. The reaction was monitored on a silicone coated plastic sheet (Merck precoated silicone 60 F254) using thin layer chromatography (TLC) using the indicated eluent. Use UV light 201026708 (254 nm) or 12 to make the dots appear. Mass spectra and accurate mass were measured using a JEOL JMS-SX/SX 102 A tandem mass spectrometer using Fast Atom Bombardement (FAB). A high-resolution FAB mass spectrometry using a resolution of 1 〇, 〇〇〇 (1〇% peak-to-valley definition) was used. Analytical HPLC was performed on a C18 column (Inertsil ODS-3, particle size 3 mm; 4.6 mm 50 mm) using the following elution gradient: a linear gradient of 5% to 95% aqueous CH3CN for 5 minutes, wherein 95 %CH3CN contained 0.04% HC02H and then a 95% CH3CN aqueous solution containing 0.04% HC02H was passed through for 2 minutes at a rate of 2.0 ml min-1. Detect the product at λ = 254 rim. Liquid Chromatography-Mass Spectrometry (LC-MS): "Method W" The LC-MS system consisted of a Waters 15 25 μ pump and a waters 2777 autosampler connected to it. The LC method is: Step Total time flow rate (μΐ/min) A(%) B(%) 0 0.2 1600 90 10 1 2.5 1600 0 100 2 2.8 1600 0 100 3 2.9 1600 90 10 4 3.10 1600 90 10 5 3.11 500 90 10

A= 100%的水和0.2%HCOOH ; B = 100% 乙腈和〇 2%HCOOH 所述自動採樣器具有1〇μ1的注射回路，注射體積為 1 Ομί。所述自動採樣器與帶有2.5 um顆粒的Waters Sunfire C18 30*4.6 mm柱連接。所述柱恒溫至室溫（約23。〇。所述 柱與Waters 2996 PDA連接。波長從240掃描至320 nm。解 析度為1.2腿’取樣速率為2〇 Hz。經過PDA之後，將物流 19 201026708 分為1 : 1並連接至Waters 2424 ELSD，其具有下列參數： 氣體壓力：40 psi ;資料速率20點/秒；放大500 ;時間常數 〇.2秒；以喷霧器方式冷卻；漂移管50°C。 樣品還採用Waters ZQ品質檢測器測量。所述質譜儀具 有下列參數：掃描範圍：117-900 a.m.u.;極性：正；資料 格式：質心；每次掃描的時間：0.500秒；中間掃描的時間： 〇·〇5秒；毛細管2.5 kV ;錐心25 V ;提取器2 V ; RF鏡頭0.5 v ;源溫125°C ;去溶劑溫度400°C ;錐心氣體100L/Hr;去 溶劑氣體800 L/Hr ; LM 1解析度15 ; HM 1解析度15 ;離子 月巨量0.5 ;倍增器500 V。整個系統由Masslynx 4.1控制。 液相色譜-質譜分析法(LC-MS): “方法H” 儀器： Alliance HT 2795，Waters 光電二極體陣列檢測器2996，Waters ZQ Single Quad » Waters/micromass PL-ELS 1000光散射檢測器，Polymer Labs LC參數： 柱 XTerra MS C18，2.5μηι，50 x 4.6 mm，Waters 保 s蔓-柱 XTerra MS C18，3.5μιη，10 x 2.1 mm，Waters 溶劑 A 0.01 M NH4Ac pH 5.0 + 5% 乙腈 溶劑B 乙腈 梯度特徵：100%A lmin恒溶劑 100%A…6 min —> 1〇〇%Β(線性或非線性 梯度，曲線4) 100%B 2 min恒溶劑 20 201026708 100%A < —1 min---- 100% A 1 min恒溶劑 10 1.0 3 100%B(線性梯度)A = 100% water and 0.2% HCOOH; B = 100% acetonitrile and 〇 2% HCOOH The autosampler has a 1 μμ1 injection loop with an injection volume of 1 μμί. The autosampler was connected to a Waters Sunfire C18 30*4.6 mm column with 2.5 um particles. The column was thermostated to room temperature (about 23. 〇. The column was connected to a Waters 2996 PDA. The wavelength was scanned from 240 to 320 nm. The resolution was 1.2 legs' sampling rate was 2 〇 Hz. After the PDA, the stream 19 201026708 is divided into 1: 1 and connected to the Waters 2424 ELSD with the following parameters: gas pressure: 40 psi; data rate 20 points/second; amplification of 500; time constant 〇.2 seconds; nebulizer cooling; Tube 50 ° C. The sample was also measured using a Waters ZQ quality detector. The mass spectrometer has the following parameters: scan range: 117-900 amu; polarity: positive; data format: centroid; time per scan: 0.500 seconds; Intermediate scanning time: 〇·〇 5 seconds; capillary 2.5 kV; cone 25 V; extractor 2 V; RF lens 0.5 v; source temperature 125 ° C; solvent temperature 400 ° C; cone gas 100 L / Hr; Solvent gas 800 L/Hr; LM 1 resolution 15; HM 1 resolution 15; ion monthly maximum 0.5; multiplier 500 V. The entire system is controlled by Masslynx 4.1. Liquid Chromatography-Mass Spectrometry (LC-MS) : "Method H" Instrument: Alliance HT 2795, Waters Photodiode Array Detector 2996, Watt Ers ZQ Single Quad » Waters/micromass PL-ELS 1000 Light Scattering Detector, Polymer Labs LC Parameters: Column XTerra MS C18, 2.5μηι, 50 x 4.6 mm, Waters s vine-column XTerra MS C18, 3.5μιη, 10 x 2.1 mm, Waters Solvent A 0.01 M NH4Ac pH 5.0 + 5% Acetonitrile Solvent B Acetonitrile Gradient Characteristics: 100% A lmin Constant Solvent 100% A...6 min —> 1〇〇%Β (linear or nonlinear gradient, curve 4 100% B 2 min constant solvent 20 201026708 100% A < —1 min---- 100% A 1 min constant solvent 10 1.0 3 100% B (linear gradient)

停止時間（min) 流速(ml/min) 注射體積（μΐ) PDA參數： 起始波長(nm) 終止波長(nm) 解析度(nm) 取樣速率（光譜/s) 探測停止時間（min) MS參數： 極性 毛細管(kV) 錐心(V) 提取器（V) RF鏡頭(V) 源溫（°C) 去溶劑溫度（°C) 錐心氣體流速(L/Hr) 去溶劑氣體流速(L/Hr) LM解析度 HM解析度 離子能量 205 350 1.2 1.000 9.00 函數1 函數 ES+ ES- 3.50 3.50 25.0 25.0 5.00 5.00 0.1 0.1 13 130 250 250 50 50 400 400 15.0 15.0 15.0 15.0 0.5 0.5 21 201026708 倍增器（V) 375 450 掃描 150-1200 150-1200 掃描持續時間（sec) 0.5 0.5 中間掃描延遲(sec) 0.3 0.3 ELSD參數： 蒸發器（°c) 80 喷霧器（°c) 80 氣體流速(SLM) 0.8 時間常數(sec) 3 實施例2 :藥理學方法 對Kvl.3鉀通道的體外抑制率：所述試驗用於確定鉀離 子通道在細胞膜内的透過性。在細胞培養中，由於錄》(Rb) 具有類似的物理-化學形式，因此其可以用作鉀的代替物。 向由附著的CHO細胞過表達的電壓門控性鉀通道Κν1·3上 負載Rb。對細胞進行去極化作用，從而使鉀通道打開，而 Rb流過所述鉀通道。這樣，上清液中的Rb濃度與鉀離子通 道透過性成正比。為了鑒定鉀通道阻斷劑，在去極化作用 之前用化合物培養細胞。上清液中Rb的減少表明存在鉀離 子通道阻斷劑。使用原子吸收光譜儀測量上清液中的Rb濃度。 在37°C/5%C02中培養CHO細胞表達的Kvl.3、Kvl.5或 hERG離子通道。在試驗之前，將細胞接種在96孔板中 (Coming，New York，USA)並培養24 h。棄去介質，並用 ΙΟΟμΙ Rb緩衝液代替介質（10 mM HEPES pH 7.4,5 mM葡萄Stop time (min) Flow rate (ml/min) Injection volume (μΐ) PDA parameters: Starting wavelength (nm) Termination wavelength (nm) Resolution (nm) Sampling rate (spectrum / s) Detection stop time (min) MS parameters : Polar Capillary (kV) Cone (V) Extractor (V) RF Lens (V) Source Temperature (°C) Desolvation Temperature (°C) Cone Gas Flow Rate (L/Hr) Desolvent Gas Flow Rate (L/ Hr) LM resolution HM resolution ion energy 205 350 1.2 1.000 9.00 Function 1 Function ES+ ES- 3.50 3.50 25.0 25.0 5.00 5.00 0.1 0.1 13 130 250 250 50 50 400 400 15.0 15.0 15.0 15.0 0.5 0.5 21 201026708 Multiplier (V) 375 450 Scan 150-1200 150-1200 Scan Duration (sec) 0.5 0.5 Intermediate Scan Delay (sec) 0.3 0.3 ELSD Parameters: Evaporator (°c) 80 Sprayer (°c) 80 Gas Flow Rate (SLM) 0.8 Time Constant (sec) 3 Example 2: In vitro inhibition of Kvl.3 potassium channels by pharmacological methods: The assay was used to determine the permeability of potassium channels in the cell membrane. In cell culture, since Rb has a similar physical-chemical form, it can be used as a substitute for potassium. Rb was loaded onto a voltage-gated potassium channel Κν1·3 overexpressed by attached CHO cells. The cells are depolarized such that the potassium channels are opened and Rb flows through the potassium channels. Thus, the concentration of Rb in the supernatant is proportional to the permeability of the potassium ion channel. To identify potassium channel blockers, cells are cultured with compounds prior to depolarization. A decrease in Rb in the supernatant indicates the presence of a potassium ion channel blocker. The concentration of Rb in the supernatant was measured using an atomic absorption spectrometer. The Kvl.3, Kvl.5 or hERG ion channels expressed by CHO cells were cultured at 37 ° C / 5% CO 2 . Prior to the experiment, cells were seeded in 96-well plates (Coming, New York, USA) and cultured for 24 h. Discard the medium and replace the medium with ΙΟΟμΙ Rb buffer (10 mM HEPES pH 7.4, 5 mM grapes)

糖 ’ 5 mM RbCl ’ 140 mM NaCl，2 mM CaCl2，1 mM 201026708Sugar ' 5 mM RbCl ' 140 mM NaCl, 2 mM CaCl 2 , 1 mM 201026708

MgSCU)。培養4 h之後，用低鉀緩衝液洗滌細胞3次（1〇 mM HEPES pH 7.4，5 mM 葡萄糖 ’ 5 mM KC卜 140 mM NaCl， 2 mM CaCl2，1 mM MgS04)。將化合物溶解在750低鉀緩 衝液中並將其加入到細胞中。12分鐘之後，加入75μΜ高卸 緩衝液對細胞進行去極性處理（1〇 HEPES pH 7.4，5 mM葡萄糖，145 mM Kd，2 mM CaCl2，1 mM MgS04)，MgSCU). After 4 h of incubation, the cells were washed 3 times with low potassium buffer (1 mM HEPES pH 7.4, 5 mM glucose '5 mM KC 140 mM NaCl, 2 mM CaCl2, 1 mM MgS04). The compound was dissolved in 750 low potassium buffer and added to the cells. After 12 minutes, the cells were depolarized by adding 75 μM high unloading buffer (1 〇 HEPES pH 7.4, 5 mM glucose, 145 mM Kd, 2 mM CaCl 2 , 1 mM MgS04).

之後再培養15分鐘。將上清液轉移至96孔板中，使用zEEnit 原子吸收光譜儀(Analytik Jena，德國）測量Rb濃度。將對照 與去極性的w/o化合物進行比較，從而確定所述離子通道抑 制率。測量進行三次。 試驗資料（1CT5厘下的％1^1.3抑制率）列在“實施例5”的 表格中（下面）。 實施例3 :通用的合成情況 ❹ όThen cultivate for another 15 minutes. The supernatant was transferred to a 96-well plate, and the Rb concentration was measured using a zEEnit atomic absorption spectrometer (Analytik Jena, Germany). The control is compared to the depolarized w/o compound to determine the ion channel inhibition rate. The measurement was performed three times. The test data (%1^1.3 inhibition rate at 1CT5 PCT) is listed in the table of "Example 5" (below). Example 3: General synthetic situation ❹ ό

(t-Boc)2〇,鹼 0°C-^20°C t_Bo〆 ό(t-Boc)2〇, base 0°C-^20°C t_Bo〆 ό

RNH2(4) MeOH MeCN 70°C HN‘RNH2(4) MeOH MeCN 70°C HN‘

,R t-Boc’ β, R t-Boc' β

GDI DMAP "MeC?T 70°C HCI, Et20GDI DMAP "MeC?T 70°C HCI, Et20

t-Bo〆 HN-/ (.HCI) 7 N- °k" 化合物9·40 可以按照描述的方法由可商購獲得的呱啶-4-酮 (piperidin-4-one)合成六氫-(1Η)-氮雜環庚三稀-4-酮 l(Roglans，Α.等，Synth. Commun. 22，1249-1258 ’ 1992; 23 201026708t-Bo〆HN-/ (.HCI) 7 N- °k" Compound 9·40 Hydrazine-(() can be synthesized from the commercially available piperidin-4-one by the method described. 1Η)-azetidin-4-one l (Roglans, Α. et al, Synth. Commun. 22, 1249-1258 ' 1992; 23 201026708

Ashwood ’ M.S.專，j· chem. Soc· Perkin Trans. I， 641-644 ’ 1995)。可以用保護基，例如叔丁氧基羰基(t_B〇c) 或苄氧基羰基(Cbz)保護1中的氨基，生成式2化合物。優 選，在驗例如氫氧化鈉水溶液或三乙胺存在下，於惰性有 機溶劑如二氣甲烷或甲醇中進行這種保護。在鹼例如氫化 納存在下使用三甲基氧化錡碘化物可以將化合物2中的羰 基部分環氧化，從而得到環氧化物3。以此方式 ，可以經4 個步驟由4-呱啶酮獲得純的環氧化物3，無需任何色譜純化 步驟。 可以按照下述方式製備標題化合物：用通式4的胺氨解 螺-環氧化物3，之後使用羰基化劑，例如羰二咪唾(CDI)使 形成的氨基醇5閉環。在該特定反應中，優選存在少量 DMAP(例如，5 mol%)，用以催化至通式6的螺噁唑烷酮衍 生物的轉化。與形成[4.5]二氮雜螺癸烷(Car〇〇n，JM等， J· Med· Chem. 1981，24，1320-1328)的類似反應相比，該 閉環反應一其中形成了 [4,6]二氮雜螺-十一烷螺環—通常進 行得更緩慢。為了提高5至6的轉化率，優選從氨基醇5中除 去剩餘的痕量原料4。對叔丁氧基羰基進行酸解可以使所得 的螺噁唑烷酮6脫保護，得到通式7的化合物。通式7的化合 物可以與羰基化試劑，例如通式8的醯氣衍生物反應，生成 式9化合物。為了清除釋放出的鹽酸，這種反應優選在驗， 例如DIPEA或三乙胺存在下，於惰性有機溶劑，例如乙腈 中進行。 特定合成方法的選擇要取決於所屬領域熟練技術人員 201026708 已知的因素，例如官能團與所用試劑的相容性、使用保護 基的可能性、催化劑、活化和偶合試劑，以及在製備的最 終化合物中存在的基本結構特徵。 使用所屬領域公知的方法，例如將本發明的化合物與適 當的酸’如無機酸或有機酸混合可以獲得藥學上可接受的鹽。 實施例3 :中間體的合成 虱4-氧代-(4H)-氮雜環庚二稀_ι_曱酸叔丁醋（2):將 φ 六氫_(4H)_氮雜環庚三烯-4-酮單鹽酸鹽(30 g，200 mmol)懸 浮在甲醇(20〇mL)中並冷卻至〇°C。滴加溶解在水(2〇ml)中 的氫氧化鈉（8.02 g，200 mmol)。逐份加入重碳酸二叔丁酯 (Boc酸酥)(43.76 g，200 mmol)，攪拌所得溶液16小時。蒸 除甲醉’將剩餘物溶解在乙謎(400 ml)和水(200 ml)中。用 水洗滌有機層、乾燥(MgS〇4)、過濾並真空濃縮，得到為棕 色油的粗2。隨後經快速色譜純化（乙酸乙酯/石油醚)得到為 淺黃色油的純2(42g，93%)。i-NMRMOOMHz，CDC13): 6 1.45(s ’ 9H ’ tBu)，1.70-1.82(m ’ 2H) ’ 2.54-2,66(m，4H)， 3.55-3.65(m，4H)。 1-氧雜-6-氮雜螺[2.6]壬烷-6-曱酸叔丁酯（3):在氮氣 氣、授拌下向三甲基氧化疏埃化物(56.1 g，255 mmol)在無 水DMSO(150 ml)的溶液中加入NaH混合物（18.5 g，1.5當 量，60%，在礦物油中）。65°C下攪拌混合物1小時，之後加 入溶於DMSO(10 ml)中的化合物2(32 g，150 mmol)的溶 液。在氮氣氛下使所述混合物回流整夜。使所述溶液達到 室溫，加入水，用***(3 X 200 ml)萃取混合物。用H2〇、 25 201026708 鹽水洗務合併的有機層，並在Na2S〇4上乾燥。蒸除Et20， 得到 82.1 g(32 g，95%)化合物 3。Α-ΝΜίΐρΟΟ MHz， CDC13) : δ(ρρηι) = 1.45(s，9H，BOC) ; 1.50-2.10(m，6H)， 2.60-2.70(m，2H)，3.5-3.60(m，2H)。 4-經基-4-[(R-l -苯基乙基氨基）甲基]-1-氮雜環庚烧曱 酸叔丁酯（5a):將螺-環氧化物3(51.5 g，226 mmol)和 (R)-(+)-l-苯基乙基胺(4a，57.68 ml，453 mmol)溶解在300 mLMeOH/MeCN，1/1 v/v中。在60°C下授拌所述溶液48小 時。用 TLC(CH2Cl2/EtOH 9/1; Rf 5a 0.4)監測反應。在二氧化 矽上真空濃縮反應混合物並用矽膠柱色譜純化（洗脫液： CH2Cl2/EtOH 95/5) ’得到為油的純的化合物5a(72 g，90%)。 3[(R)-1-苯基-乙基]-2-氧雜-3,8-二氣雜螺[4,6] Η--院 -8-甲酸叔丁酯（6a):用50.25 g(1.5當量）羰基二咪唑(CDI)處 理5a(72 g，206 mmol)在1400 mL無水MeCN中所形成的溶 液’並在70°C、氮氣氛下擾拌40小時。使溶液冷卻至室溫， 在矽膠上真空濃縮反應混合物。剩餘物用矽膠色譜純化 (CH2Cl2/EtOH 98/2)。經該操作後得到 66.0 g(85.9%)化合物6a。 3-[(11)-1-笨基-乙基]-1-氧雜_3,8-二氮雜螺[4.6]-1 烧 -2-酮(7a):向化合物6a(21.1 g，56 mmol)在水（1〇 ml)中的懸 浮液中加入4^4的鹽酸二氧己環溶液(7()1111)。4〇°(：下攪拌所 述混合物，隨後在室溫下攪拌16小時。向所述混合物中加 入二氣曱烷(200 ml) ’並用NaHC03溶液(5%，ml)洗滌 所述溶液。用DCM/MeOH，9/1(6x100 ml)洗滌水層，用水 洗條合併的有機層。將有機層蒸發至乾，得到為白色固體 201026708 的化合物7a-HCl(12.2 g，76%)，其不經進一步純化即用在 下一步驟中。^-NMRQOO MHz ’（CDC13): δ(ρρπι) = 1.55(d， 3H)，1.6-2.3(m，6H)，2.9-3.25(m，6H)，5.25(m，1H，CH)， 7.2-7.4(m，5H，H-芳族）。 按照與7a類似的方式，以螺環氧化物3和（S)-(-)-l-苯基 乙基胺朴為原料製備3-[(5)-1-苯基-乙基]-1-氧雜-3,8-二氮 雜螺[4.6] Ί--烧-2-酮7b。 光學純的非對映異構體7a和7b的製備 化合物6a和6b是兩個非對映異構體的混合物，用手性 柱色譜將其分離。用於R-混合物6a的方案（“方法A”)與用於 S-混合物6b的方案（“方法B”)不同。Ashwood ’ M.S., j. chem. Soc· Perkin Trans. I, 641-644 ’ 1995). The amino group of 1 can be protected with a protecting group such as t-butoxycarbonyl (t_B〇c) or benzyloxycarbonyl (Cbz) to form a compound of formula 2. Preferably, such protection is carried out in the presence of an aqueous solution of sodium hydroxide or triethylamine in an inert organic solvent such as di-methane or methanol. The carbonyl moiety in compound 2 can be epoxidized using trimethylsulfoxonium iodide in the presence of a base such as sodium hydride to give epoxide 3. In this way, pure epoxide 3 can be obtained from 4-acridone in 4 steps without any chromatographic purification steps. The title compound can be prepared by the following procedure: using the amine of the formula 4 to amide the spiro-epoxide 3, followed by ring closure of the amino alcohol 5 formed using a carbonylating agent such as carbonyl dimethicone (CDI). In this particular reaction, a small amount of DMAP (e.g., 5 mol%) is preferably present to catalyze the conversion to the spirooxazolidinone derivative of Formula 6. Compared with the similar reaction for forming [4.5] diazaspiroxane (Car〇〇n, JM et al., J. Med. Chem. 1981, 24, 1320-1328), the ring closure reaction is formed therein [4, 6] Diazaspiro-undecane spiro ring - usually proceeds more slowly. In order to increase the conversion of 5 to 6, it is preferred to remove the remaining trace of the starting material 4 from the amino alcohol 5. The resulting oxazolidinone 6 can be deprotected by acidolysis of the tert-butoxycarbonyl group to give the compound of the formula 7. The compound of the formula 7 can be reacted with a carbonylating agent such as an anthracene derivative of the formula 8 to give a compound of the formula 9. In order to remove the released hydrochloric acid, the reaction is preferably carried out in an inert organic solvent such as acetonitrile in the presence of, for example, DIPEA or triethylamine. The choice of a particular method of synthesis will depend on factors known to those skilled in the art, such as 201026708, such as the compatibility of the functional group with the reagents employed, the possibility of using a protecting group, the catalyst, the activation and coupling reagents, and the final compound being prepared. The basic structural features that exist. A pharmaceutically acceptable salt can be obtained by a method known in the art, for example, by mixing a compound of the present invention with a suitable acid such as a mineral acid or an organic acid. Example 3: Synthesis of intermediates 虱 4-oxo-(4H)-azepane bis-ι-decanoic acid tert-butyl vinegar (2): φ hexahydro-(4H)-azetane The ene-4-one monohydrochloride (30 g, 200 mmol) was suspended in methanol (20 mL) and cooled to EtOAc. Sodium hydroxide (8.02 g, 200 mmol) dissolved in water (2 mL) was added dropwise. Di-tert-butyl dicarbonate (Boc sour) (43.76 g, 200 mmol) was added portionwise, and the resulting solution was stirred for 16 hours. Evaporate the residue and dissolve the residue in Acrylic (400 ml) and water (200 ml). The organic layer was washed with water, dried (MgSO4), filtered and evaporated Subsequent purification by flash chromatography (ethyl acetate / pet ether) afforded 2 (42 g, 93%) as pale oil. i-NMRMOOMHz, CDC13): 6 1.45 (s '9H ' tBu), 1.70 - 1.82 (m ' 2H) ' 2.54-2, 66 (m, 4H), 3.55 - 3.65 (m, 4H). 1-oxa-6-azaspiro[2.6]decane-6-decanoic acid tert-butyl ester (3): oxidized to trimethyl sulphate (56.1 g, 255 mmol) under nitrogen gas with stirring A solution of NaH (18.5 g, 1.5 eq., 60% in mineral oil) was added to a solution of anhydrous DMSO (150 ml). The mixture was stirred at 65 ° C for 1 hour, after which a solution of Compound 2 (32 g, 150 mmol) dissolved in DMSO (10 ml) was added. The mixture was refluxed overnight under a nitrogen atmosphere. The solution was allowed to reach room temperature, water was added and the mixture was extracted with diethyl ether (3 X 200 ml). The combined organic layers were washed with H 2 〇, 25 201026708 brine and dried over Na 2 〇 4 . Evaporation of Et20 gave 82.1 g (32 g, 95%) Compound 3. Α-ΝΜίΐρΟΟ MHz, CDC13) : δ(ρρηι) = 1.45(s,9H,BOC) ; 1.50-2.10(m,6H), 2.60-2.70(m,2H), 3.5-3.60(m,2H). Tert-butyl 4-[(Rl-phenylethylamino)methyl]-1-azepane decanoate (5a): Spiro-epoxide 3 (51.5 g, 226 mmol) And (R)-(+)-l-phenylethylamine (4a, 57.68 ml, 453 mmol) was dissolved in 300 mL MeOH/MeCN, 1/1 v/v. The solution was mixed at 60 ° C for 48 hours. The reaction was monitored by TLC (CH.sub.2Cl.sub.2/.sub. The reaction mixture was concentrated in EtOAc (EtOAc) (EtOAc:EtOAc: 3[(R)-1-phenyl-ethyl]-2-oxa-3,8-dioxaspiro[4,6]indole--tert-8-carboxylic acid tert-butyl ester (6a): with 50.25 g (1.5 equivalents) of carbonyldiimidazole (CDI) was treated with 5a (72 g, 206 mmol) of a solution formed in 1400 mL of anhydrous MeCN and sparged at 70 ° C under a nitrogen atmosphere for 40 hours. The solution was allowed to cool to room temperature and the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 / EtOH 98/2). After this operation, 66.0 g (85.9%) of compound 6a was obtained. 3-[(11)-1-indolyl-ethyl]-1-oxa-3,8-diazaspiro[4.6]-1 oxa-2-one (7a): to compound 6a (21.1 g, To a suspension of water (1 〇 ml) was added 4^4 dihydrohexyl HCl solution (7 () 1111). The mixture was stirred at 4 ° C, followed by stirring at room temperature for 16 hours. Dioxane (200 ml) was added to the mixture and the solution was washed with NaHC03 solution (5%, ml). The aqueous layer was washed with aq. EtOAc (EtOAc) (EtOAc (EtOAc). Further purification is used in the next step. ^-NMRQOO MHz '(CDC13): δ(ρρπι) = 1.55(d, 3H), 1.6-2.3(m,6H), 2.9-3.25(m,6H), 5.25 (m, 1H, CH), 7.2-7.4 (m, 5H, H-aromatic). In a similar manner to 7a, spiro epoxide 3 and (S)-(-)-l-phenylethyl Preparation of 3-[(5)-1-phenyl-ethyl]-1-oxa-3,8-diazaspiro[4.6]indole-pyridin-2-one 7b from amide as an optical material. Preparation of Diastereomers 7a and 7b Compounds 6a and 6b are mixtures of two diastereomers which are separated by chiral column chromatography. Scheme for R-mixture 6a ("Method A") It is different from the scheme for S-mixture 6b ("Method B").

27 201026708 用於混合物6a的方法A。 使用製備性HPLC系統將33 g/L化合物6a的乙腈溶液分 離為非對映異構體6a(R，構型1)和6a(R，構型2)。用20μιη 的Chiralpak Τ504®作為固定相填充所述製備性HPLC柱 (250*110 mm) ’在室溫下達到平衡並用乙腈作為流動相 (570 ml/min)來洗脫。所述製備性HPLC-柱的載荷為 0.07%m/m ’流程時間約為1〇分鐘。使用UV在λ 220 nm處進 行檢測。室溫下’用基於Chiralpak 1C®，5μ(250*4.6 mm) 和甲基叔丁基Μ/乙醇混合物(95/5%V/V，lml/min)的手性分 春 析系統檢測所述分離。檢測：UV，λ 210 nm)。分析體系的 保留時間分別為9.7和11.8分鐘。 用於6b的方法B。 使用製備性HPLC系統，將6b在庚烷/乙醇混合物 (70/30%V/V)中所形成的37 g/L溶液分離為非對映異構體 6b(S ’ 構型 1)和6b(S，構型 2)。用 Chiralpak AD®，20μιη作 為固定相填充HPLC柱(250*76 mm)，在室溫下使用庚燒/乙 醇流動相（70/30%V/V ’ 270 ml/min)進行平衡和洗脫。製備 ® 性HPLC-柱的載荷為〇.2%m/m ’流過時間為約分鐘。使用 UV在λ 220 nm處進行檢測。室溫、！ ml/min的速率下，用 基於Chiralpak AD-H®，5μ(250*4.ό mm)和相同流動相的手 性分析系統檢測所述分離(檢測UV，λ 210 nm)。分析系統 的保留時間分別為5.2和8.2分鐘。 最後，與上述合成非對映異構體混合物如和北的方法 類似，對中間體6a(R，構型1)和(R，構型2)和6b(s，構型丄） 28 201026708 和（S，構型2)進行脫保護，從而得到化合物7a(R，構型1} 和(R，構型2)和7b(S，構型1)和(S ’構型2)。在該步驟中， 沒有闡明7,5稠合環系的絕對構螌。因此，將手性命名為構 型1或構型2。 實施例4 :具體化合物的合成 下面針對具體化合物的合成進行描述，其意圖進一步 詳細地說明本發明，並不意圖以任何方式限制本發明的範 圍。考慮到說明書和本文中公開的本發明的試驗，本發明 的其他實施方案對所屬領域熟練技術人員來說也將是顯而 易見的。說明書和實施例僅僅作為示例。充分詳細地描述 了一個合成的具體實施例。化合物9的所有其他製備過程都 按照類似的方式，以適當的試劑8(醯氯)和相應的中間體7 為原料來進行。 8-(3,5-三氟甲基-苯曱醯基)-3-[(R)-l-苯基-乙基]小氧 雜-3,8-二氮雜螺[4.6]十一烷-2-酮31(1R，構型1}):向化合 物7a(lR，構型 1)(4.5 g ’ 15.9 mmol)和三乙胺（3.3 ml，23.9 mmol)的乙酸乙酯（80 ml)溶液中緩慢加入3,5-(雙三氟甲基) 苯甲醯氣(3,44 ml，19.01 mmol)。室溫下攪拌混合物16小 時，之後TLC分析顯示完全反應生成一種產物（TLc洗脫27 201026708 Method A for Mixture 6a. A 33 g/L solution of compound 6a in acetonitrile was separated into diastereomers 6a (R, configuration 1) and 6a (R, configuration 2) using a preparative HPLC system. The preparative HPLC column (250*110 mm) was filled with 20 μιη of Chiralpak® 504® as a stationary phase to equilibrate at room temperature and eluted with acetonitrile as the mobile phase (570 ml/min). The preparative HPLC-column loading was 0.07% m/m' and the process time was about 1 Torr. Detection was performed at λ 220 nm using UV. Detected by chiral separation system based on Chiralpak 1C®, 5μ (250*4.6 mm) and methyl tert-butyl hydrazine/ethanol mixture (95/5% V/V, 1 ml/min) at room temperature Separation. Detection: UV, λ 210 nm). The retention times of the analytical system were 9.7 and 11.8 minutes, respectively. Method B for 6b. Separation of the 37 g/L solution of 6b in a heptane/ethanol mixture (70/30% v/v) into diastereomers 6b (S 'conform 1) and 6b using a preparative HPLC system (S, configuration 2). The column was packed with Chiralpak AD®, 20 μm as a stationary phase (250*76 mm), and equilibrated and eluted at room temperature using a heptane/ethanol mobile phase (70/30% V/V '270 ml/min). The loading of the preparative HPLC-column was 〇.2% m/m ‘the flow time was approximately minutes. Detection was performed at λ 220 nm using UV. Room temperature,! The separation was detected at a rate of ml/min using a chiral analysis system based on Chiralpak AD-H®, 5μ (250*4.ό mm) and the same mobile phase (detection UV, λ 210 nm). The retention time of the analytical system was 5.2 and 8.2 minutes, respectively. Finally, similar to the above synthetic diastereomeric mixture, such as the method of North, for intermediates 6a (R, configuration 1) and (R, configuration 2) and 6b (s, configuration 丄) 28 201026708 and (S, configuration 2) is deprotected to give compounds 7a (R, configuration 1} and (R, configuration 2) and 7b (S, configuration 1) and (S' configuration 2). In the step, the absolute structure of the 7,5 fused ring system is not elucidated. Therefore, the chirality is named as configuration 1 or configuration 2. Example 4: Synthesis of specific compounds The following describes the synthesis of specific compounds, The invention is intended to be described in further detail, and is not intended to limit the scope of the invention in any way. In view of the description and the invention of the invention disclosed herein, other embodiments of the invention will also be It is obvious that the specification and examples are by way of example only. A specific embodiment of the synthesis is described in sufficient detail. All other preparations of compound 9 are carried out in a similar manner, with the appropriate reagent 8 (indole chloride) and the corresponding intermediate. 7 is carried out as a raw material. 8-(3,5-trifluoromethyl) -Benzyl)-3-[(R)-l-phenyl-ethyl]sodium oxa-3,8-diazaspiro[4.6]undec-2-one 31 (1R, configuration 1}): Slowly add 3,5-(double to a solution of compound 7a (lR, configuration 1) (4.5 g ' 15.9 mmol) and triethylamine (3.3 ml, 23.9 mmol) in ethyl acetate (80 ml) Trifluoromethyl)benzhydrazide (3,44 ml, 19.01 mmol). The mixture was stirred at room temperature for 16 hours, then TLC analysis showed complete reaction to give a product (TLc elution

液.DCM/MeOH，99/1，v/v)。加入水(5〇 ml)，用 DCM(2 X 100 ml)萃取水層。用水（1〇〇 ml)洗滌合併的有機層，在 MgS〇4上乾燥並蒸發至乾。剩餘物經矽膠柱色譜純化(洗脫 液：DCM/MeOH，99/1 ’ v/v)，得到為油的化合物31(7.7 g， 91%)。1^-厘8:室溫2.2分鐘，[河+11]+515.1 29 201026708 絕對手性的確定。 通過振動圓二色性法球定化合物29-32和37-40的絕對 構型。VCD是一種振動光譜類型，其依賴於左和右迴圈極 化紅外輻射之間的分子吸收差別。所述技術將IR光譜學的 結構特性與立體化學的靈敏度相結合。對映異構體產生相 同的IR光譜，但卻產生符號相反的VCD光譜。使用密度函 數理論DFT計算化合物的VCD光譜。通過比較試驗和計算 光譜可以標記出絕對構型（Chemical and Engineering News，7月，18，2005，32-33)Liquid. DCM/MeOH, 99/1, v/v). Water (5 〇 ml) was added and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with water (1 mL) dried over EtOAc EtOAc The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1^-PCT 8: Room temperature 2.2 minutes, [River+11]+515.1 29 201026708 Absolute chiral determination. The absolute configuration of compounds 29-32 and 37-40 was determined by vibrating circular dichroism. VCD is a type of vibrational spectroscopy that relies on the difference in molecular absorption between the left and right circles to polarize infrared radiation. The technique combines the structural properties of IR spectroscopy with the sensitivity of stereochemistry. The enantiomers produce the same IR spectrum, but produce a VCD spectrum with opposite sign. The VCD spectrum of the compound was calculated using the density function theory DFT. Absolute configuration can be marked by comparing experiments and calculating spectra (Chemical and Engineering News, July, 18, 2005, 32-33)

C* : R^R2所連接的碳原子的構型（尺或5) C** :季螺-碳原子的構型：± =非對映異構體混合物； 1 =構型1; 2 =構型2，R = R且S = S。 使用上面給出的方案獲得物理化學和藥理學資料。C* : Configuration of the carbon atom to which R^R2 is attached (foot or 5) C**: configuration of snail-carbon atom: ± = mixture of diastereomers; 1 = configuration 1; 2 = Configuration 2, R = R and S = S. Physical and pharmacological data were obtained using the protocol given above.

Rt = LC-MS保留時間；MH+ = MH+實測值，μ = LC-MS 方法(Η或W) ’ ％ =在1〇·5μ下Κν1.3抑制率百分數 201026708Rt = LC-MS retention time; MH+ = MH+ measured value, μ = LC-MS method (Η or W) ’ % = Κν1.3 inhibition percentage at 1〇·5μ 201026708

N R. r2 c* n Rj c** m R4 R. MH+ Μ % 9 H H - 0 - 1 α-萘基 5.75 415.35 Η 37 10 H H - 0 - 2 α-萘基 5.75 415.35 Η 89 11 H H - 1 4-C1 土 α-萘基 5.94 449.11 Η 84 12 H H - 1 4-C1 1 α-萘基 5.94 449.11 Η 80 13 H H - 1 4-C1 2 α-萘基 5.94 449.11 Η 54 14 ch3 ch3 - 0 - 土 α-萘基 5.91 443.30 Η 41 15 ch3 H S 0 - 土 2 3,5-二 CF3 2.32 515.20 W 81 16 ch3 H R 0 - 土 2 3,5-二 CF3 2.20 515.10 W 77 17 ch3 H S 0 - 土 1 3-C1 5.62 413.14 Η 75 18 ch3 H S 0 - 土 1 3-CF3 2.06 447.27 W 75 19 ch3 H s 0 - 士 1 4-CF3 5.83 447.09 Η 100 20 ch3 H s 0 - 士 α-萘基 5.73 429.20 Η 82 21 ch3 H s 0 - 土 1 3-OCF3 2.12 463.22 W 98 22 ch3 H R 0 - 土 1 3-C1 5.64 413.19 Η 68 23 ch3 H R 0 - 士 1 4-CF3 5.83 447.21 Η 72 24 ch3 H R 0 - 土 α-萘基 5.75 429.25 Η 79 25 ch3 H R 0 - 土 1 3-OCF3 2.13 463.22 W 78 26 ch3 H S 1 4-C1 土 2 3,5·二 CF3 7.49 535.07 Η 55 27 ch3 H R 1 4-C1 1 2 3,5-二 CF3 6.55 548.13 Η 80 28 ch3 H R 1 4-C1 2 2 3,5-二 CF3 6.60 549.10 Η 79 29 ch3 H S 0 - S 2 3,5-二 CF3 2.21 515.10 W 100 30 ch3 H S 0 - R 2 CF3 2.26 515.10 W 75 31 ch3 H R 0 - R 2 3,5-二 CF3 2.19 515.10 W 64 32 ch3 H R 0 - S 2 3,5-:CF3 2.23 515.10 W 99 33 ch3 ch3 - 1 4-C1 土 2 3,5-二 CF3 6.69 562.15 Η 6 34 ch3 H S 1 4-C1 1 2 3,5-二 CF3 6.55 549.18 Η 87 35 ch3 H s 1 4-C1 2 2 3,5-二 CF3 6.61 549.19 Η 6 36 H H - 0 - 土 α-蔡基 5.75 415.35 Η 92 37 ch3 H R 0 - R 1 3-氰基 1.75-78 404.20 W - 38 ch3 H R 0 - S 1 3-氰基 1.77 404.20 W - 39 ch3 H S 0 - S 1 3-氰基 1.75 404.20 W - 40 ch3 H S 0 - R 1 3-氰基 1.75 404.20 W - 31 201026708 實施例6 :藥物製劑 為了臨床應用，將式（1)的化合物製成藥物組合物，其 為本發明的新實施方案，因為其含有本文中公開的化合物、 更特殊的具體化合物。可以使用的藥物組合物的類型包括： 片劑、呕嚼片、膠囊（包括微膠囊）、溶液、腸道外溶液、軟 膏(乳霜和凝膠）、栓劑和本文中公開的其他類型，或所屬々貝 域熟練技術人員由說明書和所屬領域普通知識可以 見的形式。活性成分例如還可以為混於環糊精、其鰱 内的包含配合物形式。所述組合物可以用於口服、靜脒a 皮下、氣管内、支氣管内、鼻内、肺内、經皮、經〇 腸、腸道外或其他方式給藥。所述藥物製劑含有至少 憋、N R. r2 c* n Rj c** m R4 R. MH+ Μ % 9 HH - 0 - 1 α-naphthyl 5.75 415.35 Η 37 10 HH - 0 - 2 α-naphthyl 5.75 415.35 Η 89 11 HH - 1 4-C1 soil α-naphthyl 5.94 449.11 Η 84 12 HH - 1 4-C1 1 α-naphthyl 5.94 449.11 Η 80 13 HH - 1 4-C1 2 α-naphthyl 5.94 449.11 Η 54 14 ch3 ch3 - 0 - Soil α-naphthyl 5.91 443.30 Η 41 15 ch3 HS 0 - soil 2 3,5-two CF3 2.32 515.20 W 81 16 ch3 HR 0 - soil 2 3,5-two CF3 2.20 515.10 W 77 17 ch3 HS 0 - soil 1 3-C1 5.62 413.14 Η 75 18 ch3 HS 0 - soil 1 3-CF3 2.06 447.27 W 75 19 ch3 H s 0 - 士1 4-CF3 5.83 447.09 Η 100 20 ch3 H s 0 - 士α-naphthyl 5.73 429.20 Η 82 21 ch3 H s 0 - soil 1 3-OCF3 2.12 463.22 W 98 22 ch3 HR 0 - soil 1 3-C1 5.64 413.19 Η 68 23 ch3 HR 0 - 士1 4-CF3 5.83 447.21 Η 72 24 ch3 HR 0 - earth Α-naphthyl 5.75 429.25 Η 79 25 ch3 HR 0 - soil 1 3-OCF3 2.13 463.22 W 78 26 ch3 HS 1 4-C1 soil 2 3,5·two CF3 7.49 535.07 Η 55 27 ch3 HR 1 4-C1 1 2 3,5-two CF3 6.55 548.13 Η 80 28 ch3 HR 1 4-C1 2 2 3,5-two CF3 6.60 54 9.10 Η 79 29 ch3 HS 0 - S 2 3,5-two CF3 2.21 515.10 W 100 30 ch3 HS 0 - R 2 CF3 2.26 515.10 W 75 31 ch3 HR 0 - R 2 3,5-two CF3 2.19 515.10 W 64 32 Ch3 HR 0 - S 2 3,5-:CF3 2.23 515.10 W 99 33 ch3 ch3 - 1 4-C1 soil 2 3,5-two CF3 6.69 562.15 Η 6 34 ch3 HS 1 4-C1 1 2 3,5-two CF3 6.55 549.18 Η 87 35 ch3 H s 1 4-C1 2 2 3,5-two CF3 6.61 549.19 Η 6 36 HH - 0 - soil α-Caiji 5.75 415.35 Η 92 37 ch3 HR 0 - R 1 3-cyano 1.75-78 404.20 W - 38 ch3 HR 0 - S 1 3-cyano 1.77 404.20 W - 39 ch3 HS 0 - S 1 3-cyano 1.75 404.20 W - 40 ch3 HS 0 - R 1 3-cyano 1.75 404.20 W - 31 201026708 Example 6: Pharmaceutical Formulations For clinical use, the compounds of formula (1) are formulated into pharmaceutical compositions which are novel embodiments of the invention as they contain the compounds disclosed herein, more particular specific compounds. Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, and other types disclosed herein, or The skilled person in the mussel field is in the form of a description and general knowledge in the field. The active ingredient may, for example, also be in the form of a complex comprising the cyclodextrin and its oxime. The composition can be administered orally, intravenously, intratracheally, intrabronchically, intranasally, intrapulmonarily, transdermally, transmucosally, parenterally or otherwise. The pharmaceutical preparation contains at least hydrazine,

直 (1)的化合物，並混有至少一種藥學上可接受的助劑、 劑和/或載體。在本發明的實施方案中，活性成分的絲稀釋 以為製劑的約0.1%(w/w)-約95%(w/w)， 重 0.5%-50%(w/w) ’ 優選1%-25%(W/W)。在一些實施方 活性成分的量可以大於約95%(w/w)或小於約〇1%以、中， 通過常用方法，使用輔助物質，例如液體或固 末成分，例如藥用常規液體或固體填料和膨脹劑、々、泰 乳液、潤滑劑、調味劑、著色劑和/或緩衝物質，可f劑、 發明的化合物製成適於給藥的形式。常用的輔助物W將4 碳酸鎮、二氧化鈦、乳糖、蔗糖 '山梨糖醇、甘露:包丰 和其他糖類或糖醇、滑石、乳蛋白、明膠、丨殿粉、醇’ 粉、纖維素及其衍生物、動物和植物油，例如:犴支鍵活 花軒油、花生或芝麻油、聚乙二醇，和溶劑如無^ 1 可 例如A compound of the formula (1) in admixture with at least one pharmaceutically acceptable adjuvant, agent and/or carrier. In an embodiment of the invention, the silk of the active ingredient is diluted to about 0.1% (w/w) to about 95% (w/w) of the formulation, and the weight is 0.5% to 50% (w/w) 'preferably 1% - 25% (W/W). In some embodiments, the amount of active ingredient may be greater than about 95% (w/w) or less than about 1%, by conventional means, using auxiliary substances, such as liquid or solid ingredients, such as pharmaceutically acceptable liquids or solids. Fillers and bulking agents, sputum, Thai emulsions, lubricants, flavoring agents, coloring agents and/or buffering substances can be formulated into a form suitable for administration. Commonly used auxiliary materials are 4 carbonic acid, titanium dioxide, lactose, sucrose 'sorbitol, nectar: Baofeng and other sugars or sugar alcohols, talc, milk protein, gelatin, glutinous rice powder, alcohol powder, cellulose and Derivatives, animal and vegetable oils, for example: 犴 键 活 活 活 活, peanut or sesame oil, polyethylene glycol, and solvents such as no ^ 1

32 201026708 單-或多羥基醇例如甘油，以及崩解劑和潤滑劑，例如硬脂 酸鎂、硬脂酸鈣、硬脂醯基富馬酸鈉和聚乙二醇蠟。然後 將所述混合物加工成顆粒或壓制成片劑。可以使用下列成 分製備片劑： 量(mg/片劑) To~~ 200 10 10 230 成分 化合物10 纖維素，微晶 二氧化硬，熱解 硬脂酸32 201026708 Mono- or polyhydric alcohols such as glycerin, and disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets. Tablets can be prepared using the following ingredients: Amount (mg/tablet) To~~ 200 10 10 230 Ingredients Compound 10 Cellulose, microcrystalline Dioxide hard, pyrolysis Stearic acid

總計 混合各組分並將其壓縮成片劑，每片重230 mg。 在將活性成分混合成製劑之前可以使活性成分與其他 非活性成分單獨預混合。在將所述活性成分與非活性成分 混合成製劑之前還可以使其彼此混合。 軟明膠膠囊可以用含有本發明的活性成分、植物油、 脂肪或用於軟明膠膠囊的其他適當載體的混合物來製備。 硬明膠膠囊可以含有活性成分顆粒。硬明膠膠囊還可以含 有所述活性成分以及固體粉末成分，例如乳糖、蔗糖、山 梨糖醇、甘露糖醇、馬鈴薯澱粉、玉米澱粉、支鏈澱粉、 纖維素衍生物或明膠。 用於直腸給藥的劑量單位可以製成⑴栓劑形式，其含 有混合了脂肪基質的活性物質；（ii)明膠直腸膠囊，其含有 活性物質並與植物油、石蠟油或其他適當的用於明膠^腸 膠囊的载體混合，·（iii)製成的微灌腸劑形式；或(iv)乾燥的 微灌腸劑形式，其在待給藥之前於適當的溶劑中復原。^ 液體製劑可以製成如下形式：糖漿、酏劑、濃滴劑或 33 201026708 懸浮液，例如含有活性成分和餘料的溶液或懸浮液，其中 所述餘料由例如糖或糖醇和乙醇、水、甘油、丙二醇和聚 乙二醇的混合物組成。如果希望，這種液體製劑可以含有 著色劑、調味劑、防腐劑、糖精和羧甲基纖維素或其他增 稠劑。還可以將液體製劑製成乾燥粉末形式，在使用前用 適當的溶劑將其復原。可以將用於腸道外給藥的溶液製成 如下溶液：本發明的製劑溶於藥學上可接受的溶劑中而形 成的溶液。這些溶液還可以含有穩定化成分、防腐劑和/或 緩衝成分。用於腸道外給藥的溶液還可以製成乾燥製劑， 使用前再用適當的溶劑復原。 本發明還提供可用於醫學治療的製劑和包含一個或多 個容器的“多部分試劑盒”，所述容器填充了本發明的藥物 組合物的一種或多種成分。與這種容器相關的可以是各種 書面材料，例如使用說明，或由政府機構規定的用以調節 藥品製備、使用或銷售的注意事項，該注意事項反映了該 機構許可的向人或畜給藥的製備、使用或銷售。本發明製 劑的制藥用途（其中所述藥物用於治療其中需要或希望阻 斷電壓門控性Kvl.3鉀通道的病症）和醫學治療方法包括將 治療有效總量的至少一種式（1)的化合物給予患有或易患有 其中需要或希望阻斷電壓門控性Kvl.3鉀通道的病症的病人。 【圖式簡單說明3 (無） 【主要元件符號說明】 (無） 34Total The components were mixed and compressed into tablets, each weighing 230 mg. The active ingredient can be pre-mixed separately with the other inactive ingredients prior to mixing the active ingredients into a preparation. The active ingredient and the inactive ingredient may also be mixed with each other before being mixed into a preparation. Soft gelatin capsules can be prepared with a mixture containing the active ingredient of the invention, vegetable oil, fat or other suitable carrier for soft gelatine capsules. Hard gelatin capsules may contain active ingredient granules. The hard gelatin capsules may also contain the active ingredient as well as solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. The dosage unit for rectal administration can be formulated as (1) in the form of a suppository containing the active substance in admixture with a fat base; (ii) a gelatin rectal capsule containing the active substance and in combination with vegetable oil, paraffin oil or other suitable gelatin^ The carrier of the enteral capsule is mixed, (iii) in the form of a microenema preparation; or (iv) in the form of a dried microenema which is reconstituted in a suitable solvent prior to administration. ^ The liquid preparation can be prepared in the form of a syrup, an elixir, a concentrate or a suspension of 33 201026708, for example a solution or suspension containing the active ingredient and the remainder, wherein the remainder is made, for example, of sugar or sugar alcohol and ethanol, water , a mixture of glycerin, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin, and carboxymethylcellulose or other thickening agents. It is also possible to prepare the liquid preparation in the form of a dry powder which is reconstituted with a suitable solvent before use. The solution for parenteral administration can be prepared as a solution in which the preparation of the present invention is dissolved in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration can also be prepared as a dry preparation which can be reconstituted with a suitable solvent before use. The invention also provides a formulation useful for medical treatment and a "multipart kit" comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such containers may be various written materials, such as instructions for use, or precautions prescribed by government agencies to regulate the preparation, use, or sale of the drug, which precautions permit the administration of the device to humans or animals. Preparation, use or sale. Pharmaceutical use of a formulation of the invention, wherein the medicament is for treating a condition in which a voltage-gated Kvl.3 potassium channel is required or desired to be blocked, and a medical treatment method comprising at least one formula (1) of a therapeutically effective total amount The compound is administered to a patient suffering from or susceptible to a condition in which a voltage-gated Kvl.3 potassium channel is required or desired to be blocked. [Simple diagram 3 (none) [Description of main component symbols] (none) 34

Claims (1)

201026708 七、申請專利範圍： 1. -種式⑴的化合物，或互變異構體、立體異構體，或前 述任一種的藥理學上可接受的鹽，201026708 VII. Patent application scope: 1. A compound of the formula (1), or a tautomer, a stereoisomer, or a pharmacologically acceptable salt of any of the foregoing, 其中： -RjaR2獨立地為氫、氘、氟、CF3或烷基(Cu)， 所述烧基(Cw)未被取代或被一個或多個氟原子取代， -η為〇(零）、1或2， -R3選自鹵素、烷基(U、CF3、CN、NH2、NHAc、 OH、OCH3 或 〇CF3， -m為 0(零）、1、2或 3， -R4選自鹵素、烷基(Cu)、CF3、CN、NH2、NHAc、 OH、OCH3或OCF3，或(R4)m與其所連接的苯環—起形成 萘基。 2.如申請專利範圍第1項的化合物，或互變異構體、立體 異構體’或前述任一種的藥理學上可接受的鹽，其中心 和R2獨立地為氫或甲基，η為0(零）或1，r3為氫，111為1 或 2 ’ 且R4選自齒素、CF3、CN、〇CH3 或 〇CF3，或(R4)m 與其所連接的苯環·一起形成蔡基。 35 201026708 檨I*，月專Γ範圍第1項的化合物或互變異構鱧、立體異 ’或則述任一種的藥理學上可接受 物選自： ()8 [3,5-雙(二氟甲基)苯甲醯基]小苯基 基]1氧雜-3,8-二氮雜螺[4 6]十一烧_2酮， (5办8-[3’5-雙(三氟甲基)苯甲酿基] 3 [(is)小苯基 乙基H-氧雜-3,8-二氮雜螺[46]_十—烧_2酮， (5R) 8-[3,5-雙(三氟甲基)苯甲酿基]·3_[(1R)小苯基 乙基η-氧雜_3,8_二氮雜螺[46]_十一烧_2_嗣， φ (5S)_8_[3,5-雙(三氟甲基)苯甲醯基]-3-[(lR)-l-苯基 乙基]-1-氧雜_3,8-二氮雜螺[4.6]-十一烷_2_酮， (5S)-8-[3-氰基苯甲醯基ρίκα)」·苯基乙基]^氧 雜—3,8_二氮雜螺[4.6]十一烷-2-酮， (5R)-8-[3-氰基苯甲酿基]_3-[(lS)-l-笨基乙基]小氧 雜-3,8-二氮雜螺μ.6]十一烷-2-酮， (5R)-8-[3-氰基苯甲酿基]-3-[(lR)-l-苯基乙基]小氧 雜-3,8-二氮雜螺[4.6]十一烷_2-酮， ® (5S)_8-[3-氰基苯甲醯基]-3-[(lR)-l-苯基乙基]-1-氧 雜-3,8-二氮雜螺[4.6]十一烷-2-酮。 4. 如申請專利範圍第1或2項所述的化合物，或其藥理學上 可接受的鹽，所述化合物為光學活性的對映異構體或非 對映異構體。 5. 如申請專利範圍第丨或2項所述的化合物，或其藥理學上 可接受的鹽，其中與噁唑烷酮環上的氮原子相連的碳原 36 201026708 子是(R)或(S)對映異構體。 6. 如申請專利範圍第1或2項所述的化合物，或其藥理學上 可接受的鹽，其中所述中心季螺-碳原子為(R)或(S)對映 異構體。 7. —種式(v)的化合物，Wherein: -RjaR2 is independently hydrogen, hydrazine, fluorine, CF3 or alkyl (Cu), the alkyl group (Cw) is unsubstituted or substituted by one or more fluorine atoms, -η is 〇 (zero), 1 Or 2, -R3 is selected from halogen, alkyl (U, CF3, CN, NH2, NHAc, OH, OCH3 or 〇CF3, -m is 0 (zero), 1, 2 or 3, -R4 is selected from halogen, alkane a base (Cu), CF3, CN, NH2, NHAc, OH, OCH3 or OCF3, or (R4)m forms a naphthyl group with the benzene ring to which it is attached. 2. A compound as claimed in claim 1, or An isomer, a stereoisomer, or a pharmacologically acceptable salt of any of the foregoing, wherein the center and R2 are independently hydrogen or methyl, η is 0 (zero) or 1, r3 is hydrogen, and 111 is 1 Or 2 ' and R4 is selected from dentate, CF3, CN, 〇CH3 or 〇CF3, or (R4)m together with the benzene ring to which it is attached to form a Tsai. 35 201026708 檨I*, month special range item 1 The compound or tautomeric oxime, stereoisomeric or any of the pharmacologically acceptable substances selected from the group consisting of: () 8 [3,5-bis(difluoromethyl)benzylidene] small phenyl group ]1 oxa-3,8-diazaspiro[4 6]undecazine_2 ketone, (5 do 8- [3'5-bis(trifluoromethyl)benzoyl] 3 [(is) small phenylethyl H-oxa-3,8-diazaspiro[46]_deca-xan-2-one , (5R) 8-[3,5-bis(trifluoromethyl)benzyl]·3_[(1R) small phenylethyl η-oxa-3,8-diazaspiro[46] _11烧_2_嗣, φ (5S)_8_[3,5-bis(trifluoromethyl)benzylidene]-3-[(lR)-l-phenylethyl]-1-oxo Hetero-3,8-diazaspiro[4.6]-undecane-2-one, (5S)-8-[3-cyanobenzylidene ρίκα)·phenylethyl]^oxa- 3,8-diazaspiro[4.6]undecyl-2-one, (5R)-8-[3-cyanobenzoyl]_3-[(lS)-l-stupylethyl] small Oxa-3,8-diazaspiro-[6]undec-2-one, (5R)-8-[3-cyanobenzoyl]-3-[(lR)-l-benzene Ethylethyl]sodium oxa-3,8-diazaspiro[4.6]undecane-2-one, ® (5S)_8-[3-cyanobenzylidene]-3-[(lR) -l-phenylethyl]-1-oxa-3,8-diazaspiro[4.6]undec-2-one. 4. The compound of claim 1 or 2, or a pharmacologically acceptable salt thereof, which is an optically active enantiomer or diastereomer. 5. A compound as described in claim 2 or 2 Or a pharmaceutically acceptable salt thereof, wherein the carbon and nitrogen atom attached to the original oxazolidone ring 36201026708 promoter is (R) or (S) enantiomer. 6. The compound of claim 1 or 2, wherein the central quaternary-carbon atom is the (R) or (S) enantiomer, or a pharmacologically acceptable salt thereof. 7. a compound of formula (v), 其中Ri、R2、η和R3具有如中請專利範圍第1項中給 出的含義，這種化合物可用於合成式（1)的化合物。 8. —種式(vi)的化合物，Wherein Ri, R2, η and R3 have the meanings given in item 1 of the scope of the patent application, and such a compound can be used for the synthesis of the compound of the formula (1). 8. a compound of formula (vi), 其中R!、R2、η和R3具有如申請專利範圍第1項中給出 的含義，這種化合物可用於合成式（1)的化合物。 9. 一種式(vii)的化合物， 37 201026708Wherein R!, R2, η and R3 have the meanings given in the first item of the patent application, and such a compound can be used for the synthesis of the compound of the formula (1). 9. A compound of formula (vii), 37 201026708 其中I、R2、η和R3具有如申請專利範圍第1項中給 出的含義，這種化合物可用於合成式（1)的化合物。 10.如申請專利範圍第9項所述的化合物，所述化合物為：Wherein I, R2, η and R3 have the meanings given in the first item of the patent application, and such a compound can be used for the synthesis of the compound of the formula (1). 10. The compound of claim 9, wherein the compound is: 11. 一種製備如申請專利範圍第1項所述的化合物的方法， 包括下述步驟： (i)用保護基保護六氫（1H)-氮雜環庚三烯-4-酮1的 氨基，得到式2的酮：11. A process for the preparation of a compound according to claim 1, comprising the steps of: (i) protecting the amino group of hexahydro(1H)-azephen-4-one 1 with a protecting group, The ketone of formula 2 is obtained: (ii)將式2的酮環氧化為式3的螺-環氧化物：(ii) epoxidation of the ketone of formula 2 to the spiro-epoxide of formula 3: 2 3 (vi)用式RNH2的胺4氨解式3的螺-環氧化物，得到 式5的氨基醇，其中R代表如下部分： 38 2010267082 3 (vi) Aminolysis of the spiro-epoxide of the formula 3 with the amine 4 of the formula RNH2 gives the amino alcohol of the formula 5, wherein R represents the following moiety: 38 201026708 其中Rj〇R2獨立地為氫、氘、氟、CF3或烧基(Cw)， 所述烷基(C^)未被取代或被一個或多個氟原子取代；^ 為〇(零）、1或2 ; R3選自鹵素、烷基(Q.3)、CF3、CN、 NH2、NHAc、OH、OCH3 或 OCF3 ; m為 0(零）、卜 2或 3，Wherein Rj〇R2 is independently hydrogen, deuterium, fluorine, CF3 or alkyl (Cw), the alkyl (C^) is unsubstituted or substituted by one or more fluorine atoms; ^ is 〇 (zero), 1 Or 2; R3 is selected from halogen, alkyl (Q.3), CF3, CN, NH2, NHAc, OH, OCH3 or OCF3; m is 0 (zero), 2 or 3, (vii)在羰基化試劑存在下，經DMAP催化使氨基醇 5閉環形成螺-噁唑烷酮衍生物6(vii) ring closure of the amino alcohol 5 to form the spiro-oxazolidinone derivative 6 in the presence of a carbonylation reagent by DMAP catalysis (viii)將式6的螺惡嗤院酮脫保護，得到式7的化合物。 12·如申請專利範圍第11項使述的方法，其中所述保護基選 自苄氧基羰基(Cbz)或叔丁氧基羰基(t_B〇c)。 13. —種藥物，所述藥物包含如申請專利範圍第1裘11項中 任一項的化合物或其藥理學上可接受的鹽。 14. 一種如申請專利範圍第Μ1中任一項的化合物用於製 39 201026708 備藥物組合物的用途，其中所述藥物組合物用於治療糖 尿病和炎症性神經病，包括T-細胞介導的自身免疫疾 病，例如類風濕性關節炎和多發性硬化。 15. —種藥物組合物，所述組合物包含至少一種藥學上可接 受的載體，或至少一種藥學上可接受的輔助物質，或其 兩種或更多種的組合；和藥理學活性量的至少一種如申 請專利範圍第1-11項中任一項的化合物或其藥理學上 可接受的鹽。(viii) Deprotection of the snail ketone ketone of formula 6 to give a compound of formula 7. 12. The method of claim 11, wherein the protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (t_B〇c). A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt thereof. 14. Use of a compound according to any one of claims 1 to 1 for the preparation of a pharmaceutical composition for the treatment of diabetes and inflammatory neuropathy, including T-cell mediated self Immune diseases such as rheumatoid arthritis and multiple sclerosis. 15. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, or at least one pharmaceutically acceptable auxiliary substance, or a combination of two or more thereof; and a pharmacologically active amount A compound or a pharmacologically acceptable salt thereof, according to any one of claims 1 to 11. 40 201026708 四、指定代表圖·· 、 (一) 本案指定代表圖為：第（ ）圖。 (二) 本代表圖之元件符號簡單說明：40 201026708 IV. Designation of Representative Representatives·· (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 22